Periodontology 2000, Vol.

22, 2000, 2243 Printed in Denmark All rights reserved

Copyright C Munksgaard 2000

PERIODONTOLOGY 2000
ISSN 0906-6713

Fundamental principles affecting the outcomes of therapy for osseous lesions

K ENNETH S. K ORNMAN & PAUL B. R OBERTSON
Therapies for treating moderate to severe periodontitis have often been judged based on the ability of the therapy to improve osseous lesions. The effectiveness of scaling and root planing or surgical access for root planing plus regular maintenance care in moderate to severe periodontal disease cases has been well established over many years (28, 92, 108, 166). The landmark studies, which claried basic principles for the successful treatment of adult periodontitis, evaluated the therapies that were in standard clinical use during the 1960s, 1970s and 1980s. Those therapies primarily focused on gingivectomy, curettage, scaling and root planing, surgical access aps and resective osseous surgery. All the studies concluded that successful clinical outcomes could be achieved, in general, if 1) the clinician thoroughly and regularly removed the bacterial deposits from the root surfaces, and 2) the patient kept the supragingival areas clean. In the past 15 years two new observations have had an impact on our thinking relative to outcomes of periodontal therapy: O Despite the general effectiveness of the basic therapeutic concepts outlined above, there is substantial variation in clinical response, especially in more severely involved sites. This has led to a need to understand the major factors that contribute to the variance. O New surgical techniques, involving membranes and grafting materials, have been developed and provide options for regenerating soft and hard tissues, such that in some areas pockets can be reduced without resective procedures. It is therefore appropriate to review the basic elements that inuence therapeutic outcomes in osseous lesions. Due to the focus of clinical research in the past 10 years, many of these factors have been evaluated relative to guided tissue regeneration procedures. For that reason, guided tissue regeneration therapy will be used as the reference point for this discussion. It should also be noted that, although the term osseous lesion refers to bone, most clinical data are available as measurements of clinical attachment level. In most clinical research, apparent gain in clinical attachment level is usually the endpoint for comparison of therapies; it is therefore difcult to discuss the inuence of risk factors relative to resective surgery. This chapter discusses the factors that inuence the outcomes of therapy for osseous lesions. Since most of our knowledge in this area has come in the past 15 years, guided tissue regeneration procedures are used as the focal point for discussing the fundamental principles that affect outcomes. Other chapters in this volume discuss the role of different devices and surgical techniques for managing osseous lesions. With the introduction of new surgical procedures, the operative technique itself is always considered a critical determinant of the clinical outcomes. Surgeons who are experienced in a procedure may be expected to achieve a generally better response than those less experienced with the procedure. It is certainly reasonable that, with new procedures, critical details of the surgical technique must be determined as one means of improving surgical outcomes and reducing variability. However, the surgical technique often implicitly includes case selection, which may vary greatly among surgeons. Once an appropriate indication and basic surgical techniques for the new procedure are established, it becomes possible to evaluate factors unique to different patients and different sites that inuence the clinical outcomes. This involves data-based clarication of

22

Outcome of therapy for osseous lesions

the factors that inuence the variability in clinical outcomes following a surgical procedure. Biological phenomena that involve complex interactions among many factors are often explored in a sequential series of studies, and therapies for osseous defects have followed that path. Guided tissue regeneration studies are used as an example. The rst regenerative studies were proof-of-principle studies designed to demonstrate that it is possible, under certain conditions, to actually regenerate the periodontal tissues. Proof-of-principle studies are usually done under very limited conditions that intentionally do not reect the broad range of clinical situations that will be encountered in practice. The next series of regenerative studies began to look, in a controlled fashion, at the actual magnitude of benet that could be expected compared to other therapies. The rst series of controlled studies not only involved relatively short-term follow-ups but also set limiting patient and site criteria in order to properly control the variance in the results. As regenerative therapy moved into more widespread use, more variation in clinical outcomes were reported than were reected in early, tightly controlled, studies. Fortunately, at this point in the clinical experience with regenerative therapy, dedicated investigators have initiated long-term studies to both explore the long-term outcomes and to better understand how major factors contribute to the variability in clinical experiences. It is not uncommon, as has been done with regenerative therapy, for this latter stage to only be initiated after 10 to 15 years of clinical use. We are fortunate that sufcient data and experi-

ence now exist to provide substantial understanding of some of the factors that contribute to the clinical success of therapy for osseous defects. Risk factor studies usually involve statistical association techniques that provide condence that a particular factor and a clinical result are related, but the statistical techniques do not determine whether the risk factor is causative or how the factor is biologically involved in the outcome. Those understandings of the specic role played by a risk factor become critical to the development of clinical strategies to improve outcomes.

A small group of factors appear to inuence the outcomes of periodontal therapy for osseous defects (Fig. 1)
One approach to exploring the role of risk factors is the construction of inuence diagrams that are developed by interpreting both the biology and the clinical trial ndings. It should be emphasized that inuence diagrams always begin as theoretical structures with varying degrees of data and should be rened as more data become available. Those diagrams serve as a mechanism for designing future studies and for interpreting past data. Based on currently available data and knowledge, we suggest that the primary factors that inuence the successful management of osseous defects may be classied as: 1) bacterial contamination, 2) innate wound healing potential, 3) local site characteristics

Fig. 1. Factors inuencing treatment outcomes for osseous lesions

23

Kornman & Robertson

and 4) surgical procedure. It should be noted that these specic factors may inuence various aspects of human biology but are only listed with reference to how they inuence the therapeutic response of osseous defects. Some aspects of innate wound healing potential may not be relevant to the actual clinical outcomes in osseous defects and therefore should not be included in the diagram. The specic roles of different surgical devices and procedures are discussed elsewhere in this volume. An inuence diagram is a formal diagrammatic tool for representing conditional relationships between entities (213). Although inuence diagrams may be used to develop decision trees and may be solved mathematically, this diagram will be used merely to guide the discussion of how various factors inuence regeneration. The outcome, shown on the far right of Fig. 1, is the success of therapy, which may be expressed as a linear measurement of bone or attachment level change or some qualitative assessment. The rst line of bubbles to the left of the outcome represents the categories of factors, including bacterial contamination, innate wound healing potential, surgical procedure and site characteristics, that inuence the outcome. For each category, the bubbles to the left represent specic factors that inuence the overall nature of that category of factors. For example, innate wound healing potential may be inuenced by age, smoking, genetics and other factors. Most of the following discussion uses regenerative therapy as the reference point for evaluating factors that inuence therapeutic outcomes. Some excellent reviews of the factors involved in the success of regeneration have been previously published and provide additional perspective on some of the topics discussed below (23, 31, 54, 118).

tion of collagen and bone (149). In addition to activation of actual destructive phases of collagen and bone, the same host mediators also have been shown to reduce collagen synthesis and bone formation (144, 149). It is therefore very reasonable to expect that similar bacterial accumulations following regenerative procedures would result in a reduced net formation of connective tissue and bone. Several studies support that view (29, 30, 80, 117).

Bacteria associated with periodontitis attach to and are found on membranes used in regenerative therapy Tissue-implanted materials, such as guided tissue regeneration membranes, encourage bacterial contamination of the local site (152). Mombelli et al. (130) evaluated the microbial contamination of expanded polytetrauoroethylene membranes 6 weeks after surgical placement in ten patients. Patients received diligent professional monitoring during the postoperative healing phase, including professional cleaning at least every week and home rinsing with chlorhexidine (0.1%). Surgical results were described as clinically successful, yet gram-negative anaerobic rods, commonly associated with adverse periodontal conditions, were found in all samples. Porphyromonas gingivalis was found at high levels in one patient, and Prevotella intermedia was found in six of the nine patients. The authors concluded that guided tissue regeneration membranes appeared to harbor periodontal pathogens on a frequent basis. Several investigators have found relatively high levels of bacterial contamination of expanded polytetrauoroethylene membranes (64, 140, 202, 207, 221). Others (131) have reported that guided tissue regeneration sites during the active healing phase were more likely to be colonized by periodontal bacteria than sites treated without membranes. The clinical characteristics of the surgical site may initially contribute to the bacterial contamination and then lead to further complications in healing. In clinical sites with submerged barrier membranes, periodontal pathogens were not present by various detection techniques, whereas high proportions of P . gingivalis, Actinobacillus actinomycetemcomitans and Peptostreptococcus micros were found in exposed membranes with minimal bone regeneration (139). The type of membrane used for regeneration in human subjects, including collagen, expanded polytetrauoroethylene and polylactic acid, does not seem to inuence the colonization by various periodontal bacterial species (27, 231).

Bacterial contamination (Fig. 1, node 1.0)

It is well established that plaque control is a critical determinant of the success or failure of various outcomes of periodontal therapy (6, 28, 109, 141, 170, 185). In addition, specic plaque bacteria have been shown to initiate periodontitis, to be involved in the progression of the disease, and to inuence outcomes of therapy (74, 171, 240). The bacterial effects on disease include an activation of cytokines such as interleukin-1b, prostanoids such as prostaglandin E2, and enzymes such as matrix metalloproteinases that activate destruc-

24

Outcome of therapy for osseous lesions

Bacteria associated with periodontitis are known to modulate connective tissue and bone metabolism The inuence of periodontal bacteria on connective tissue and bone have been reviewed recently (144, 178, 199).

Inadequate plaque control, or the presence of specic bacteria, have been associated with less favorable clinical outcomes following regenerative therapy (Fig. 1, node 1.1)
The benets of plaque control in the response to periodontal therapy are well accepted (28, 109, 141, 170). Experimental studies of guided tissue regeneration in monkeys have explored the inuence of membrane exposure to bacterial plaque on the healing of the lesions. In one study (193) experimental periodontal lesions were created and the guided tissue regeneration membranes were either completely covered by soft tissue or left exposed by 2 mm. After 6 months of healing, histological evaluation showed that the covered guided tissue regeneration membranes had new connective tissue and bone corresponding to 67% to 100% of the initial depth of the defect, whereas the healing under exposed membranes ranged from 30% to 59% of the defect depth. Although this study suggests a major role for the bacteria in less complete regeneration, the exposed membrane also introduces additional complications relative to healing, such as differences in revascularization. The clinical effects of plaque control have been well described in longitudinal studies of guided tissue regeneration procedures. In one 4-year study of 23 patients (30), guided tissue regeneration procedures resulted in a mean gain of 4.1 mm of clinical attachment level after 1 year of strict plaque control. This clinical outcome was stable for an additional 3 years in 15 patients who adhered to a regular recall program every 3 months. In the other 8 patients who received sporadic maintenance care, a mean of 2.8 mm of the 1-year gain was lost in the next 3 years. In addition, P . gingivalis and P . intermedia were detected more frequently in the sporadic care group. Machtei et al. (117) surgically reentered mandibular class II furcations that had been treated with guided tissue regeneration therapy and evaluated the success factors. They determined that the opti-

mal gain in attachment level and the amount of new bone were observed in sites that met the following criteria: 1) deeper sites, 2) good oral hygiene, 3) minimal inammation, 4) no detectable A. actinomycetemcomitans and 5) the presence, by microscopy, of connective tissue cells on the inner surface of the membrane. In a similar 1-year longitudinal study (46), 47% of the variability in clinical attachment level could be explained by defect characteristics, early membrane exposure and the presence of plaque in the area. The presence of plaque in the local area was associated with signicantly less clinical attachment level gain and less bone ll. Others (80) have noted that high plaque levels were present in many of the class II furcations that were treated with guided tissue regeneration procedures but did not respond favorably. One study in monkeys (110) indicated that sites with plaque accumulation previously treated by guided tissue regeneration procedures have less inammation than sites that never had periodontitis. Although there are exceptions (70), several studies (46, 137139, 200, 208) support the conclusion that less favorable clinical outcomes to guided tissue regeneration procedures are associated with increased bacterial contamination. Of the success factors that are controllable at a given site, bacterial contamination appears to have a major inuence on outcome.

Antibacterial therapies offer some promise, but interpretation of the clinical data is complicated (Fig. 1, node 1.2)
Since bacterial contamination appears to adversely affect the clinical outcome of regenerative procedures, it seems logical to expect antimicrobial therapy to provide clinical benets during procedures designed to treat osseous defects. Although that conclusion is not yet supportable by the data, a few studies provide some promising insights. Some experienced investigators in this area (61) have concluded that systemic antibiotics, presented at the time of surgery, appear to offer no advantages in terms of clinical outcome. The multiple factors that inuence long-term outcomes of regenerative therapy also complicate the evaluation of antimicrobial therapy in regeneration studies. For example, exposure of the membrane during the healing phase and poor patient home care or compliance with professional care may produce such

25

Kornman & Robertson

overwhelming inuences on bacterial contamination that short-term use of antimicrobial agents should not be expected to change the total equation. It should also be noted that some studies have routinely used antibiotics as part of the surgical procedure, but they have not specically focused on the role of antimicrobial agents in the clinical outcome. Various approaches to the use of antimicrobial agents in regenerative procedures have been discussed (136). Patients treated with guided tissue regeneration procedures plus a systemic antibiotic during the healing phase (131) achieved more horizontal gain in clinical attachment and more gain in bone density than patients treated with guided tissue regeneration procedures but no antibiotic. Clinical benets associated with antibiotics have also been shown by others (137). Some investigators (35, 36) have shown no clinical advantage after one year with the systemic use of 10 days of amoxicillin/ clavulanic acid. Local antimicrobial therapies applied topically to the site at the time of surgery or postoperatively have also been evaluated. Local metronidazole gel applications during guided tissue regeneration procedures produced a reduction in bacteria at the site, as compared with controls, for 1 week. At the end of a 2-week period, there were no bacterial differences between test and control groups (50). It should be noted, however, that this same study had a dramatic benet associated with antimicrobial use (192). In 12 patients with paired vertical defects, one site in each patient was treated with guided tissue regeneration membranes plus local application of metronidazole gel. The control site was treated with the membrane alone. At 6 months there were no signicant differences in plaque levels, but the metronidazole sites had a median gain of 92% of the defect depth compared with 50% of the control defect. Local irrigation with tetracycline during the surgical procedure (116) did not produce a clinical difference from saline irrigation, but sites that retained or recolonized with A. actinomycetemcomitans tended to have worse clinical outcomes after 1 year. Chlorhexidine has been used routinely to reduce bacterial contamination of guided tissue regeneration membranes. In one study (209), a clever experimental device was used to evaluate membranes treated with either topical chlorhexidine or no antibacterial agent while they were exposed to the oral environment. The device did not cover surgical sites. Chlorhexidine substantially reduced bacterial colonization of the membranes and altered the mixture of bacterial morphologies found attached to the mem-

brane. It should be noted, however, that on exposed guided tissue regeneration membrane surfaces bacteria will accumulate even when the patient is treated with antimicrobial agents. In 8 patients treated with a synthetic penicillin derivative plus chlorhexidine (0.2%) rinses (64), the exposed membrane had dense bacterial layers with various morphotypes, including lamentous bacteria and spirochetes. One specimen included microscopic structures suggestive of fungal growth.

Smoking inuences the bacterial composition of the plaque (Fig. 1, node 1.3)
For many years clinicians were aware that patients who smoked often had less favorable healing or a prolonged healing after periodontal surgery. For several years investigators (1013, 47, 62, 71, 72, 85, 106) reported adverse effects of smoking on periodontal disease in general. These observations gradually coalesced into a coherent view that implicated smoking as a major risk factor for periodontal disease.

Smoking is associated with more severe periodontitis In epidemiological health surveys (the US National Health and Nutrition Examination Survey) after controlling for the effects of age and oral hygiene, smoking was found to be signicantly associated with severe periodontal disease (85). In more recent studies of the role of various risk factors and periodontal disease, smoking was strongly associated with increased loss of attachment and bone (65, 66). In fact, after age, plaque and calculus, race, gender and systemic disease were controlled, smoking was the strongest predictor of disease severity. In addition, when serum cotinine levels, an objective biochemical marker of smoking, was assayed in 79 patients, the level of cotinine was positively correlated with both clinical attachment level and bone crest height (60). This topic has been discussed in excellent recent reviews (55, 144).

Smoking is associated with adverse healing after therapy or less favorable clinical responses Preber & Bergstrom (161163) have reported that scaling and root planing in smokers resulted in less reduction in bleeding and less reduction, although not sig-

26

Outcome of therapy for osseous lesions

nicantly so, in probing depth. They also (164) reported that surgery in smokers resulted in signicantly less reduction in probing depth than in nonsmokers, when responses were adjusted for plaque levels. Recently, this same group (166) has shown that, following nonsurgical therapy, sites 4 mm were reduced by 57% in nonsmokers and 40% in smokers. Smokers were dened as subjects smoking at least 15 cigarettes per day (mean 21.8). Nonsmokers denied ever smoking. No bacterial differences were observed between smokers and nonsmokers. In another study (68), subjects with established periodontitis were treated by scaling and root planing and plaque control. After therapy, nonsmokers and former smokers had a 7.2% and 7.1% reduction in pockets 5 mm, respectively, whereas deep pockets in current smokers decreased by 4.8%. In addition, after therapy, P . gingivalis was not detectable in 75% of nonsmokers, 92% of former smokers and 33% of current smokers, strongly suggesting that smokers are less capable of eliminating pathogens. These ndings are in contrast to other reports of no inuence of smoking on reduction of P . gingivalis (166). In a longitudinal study of periodontal therapy, smokers had signicantly less improvement in both probing depth and clinical attachment level than nonsmokers (1). These ndings were consistent throughout the 6 years of maintenance therapy. Smokers in this study were dened as 10 cigarettes per day.

response relationship to smoking (65, 66). Some studies have found a relationship between the level of smoking and treatment response (91), but other studies of treatment response (68) did not nd a relationship to amount of current smoking, measured either as pack-year history or current cigarettes per day. Other clinical observations (129, 226) have noted a signicant smoking effect on outcome in patients smoking 10 cigarettes per day. This is of great importance for regenerative therapy, because it demonstrates that smoking cessation, and perhaps smoking reduction, are important considerations as part of the therapy plan. This clinical observation was made by Miller (129) who, in describing factors that contribute to less favorable outcomes with free gingival grafts to cover root surfaces, reported a ... 100% correlation between failure to obtain root coverage and heavy smoking. He goes on to note that After this correlation was made, heavy smokers were requested to refrain from smoking during the initial healing phase (2 weeks). In those who did refrain, the level of root coverage was comparable to that of non-smokers. Grossi et al. (68) have concluded that: ... merely ceasing to smoke before periodontal therapy increases the likelihood of better treatment outcome.

Smoking is associated with less favorable regeneration outcomes In a retrospective analysis of a longitudinal study of guided tissue regeneration procedures in class II furcations, Rosenberg & Cutler (183) reported a 42% failure rate after at least 4 years. Of those failures, however, 80% were in patients who smoked at least 10 cigarettes per day for 5 years. As part of an extensive clinical study to dene success criteria and determinants for regeneration, Tonetti et al. (226) determined the inuence of smoking on regeneration outcomes. At 1 year after guided tissue regeneration surgery, smokers (10 cigarettes per day) had a signicantly less favorable gain in probing attachment level than did nonsmokers. The probing attachment level gain in nonsmokers was 5.21.9 mm compared with 2.11.2 mm gain in smokers (P0.0001). This effect remained signicant after adjustment for different plaque levels and baseline differences in defect anatomy. Approximately 62% of the variance in the probing attachment level outcome could be explained by the baseline depth of the infrabony defect, smoking status and oral hygiene. Of great interest was the assessment of factors involved in an un-

Cessation of smoking improves the response to periodontal therapy Studies of heart disease risk have shown that the cumulative smoking exposure over time was a strong risk factor. The degree of cumulative exposure is usually expressed as pack-years history calculated by multiplying the number of packs of cigarettes (20 cigarettes per pack) smoked per day times the number of years smoked. Although this approach gives some perspective on risk for cumulative damage to various organs, it does not reect risk for future disease or response to current therapy. This becomes very evident when one compares current smokers and smokers who no longer smoke. Recent reports (68) indicate that, although current smokers have worse clinical and microbiological responses to therapy than individuals who have never smoked, former smokers with comparable smoking histories to the current smokers were no different from those who had never smoked. Cumulative periodontal destruction shows a dose-

27

Kornman & Robertson

favorable healing response. Smoking produced a 4.3fold increased risk of an unfavorable response. In patients who were nonsmokers and had good oral hygiene, only 8.7% of the sites had an unfavorable outcome after one year. In patients who were smokers, had poor oral hygiene, or both risk factors, 43.8% to 62.5% of the sites had an unfavorable response. In a 5-year follow-up in a controlled study (32), guided tissue regeneration therapy was compared to root planing alone. In most cases both the guided tissue regeneration site and the control site in each patient responded concordantly. Patients in which both sites remained stable were characterized by good oral hygiene, compliance with recall, and nonsmoking status. Those in which both sites showed deterioration tended to be smokers with oral hygiene that deteriorated during the follow-up period. The specic mechanisms by which smoking inuences regeneration are not known The mechanisms by which smoking inuences the clinical outcomes of regenerative procedures are purely speculative, but many of the known biological effects of smoking would certainly be expected to adversely inuence both periodontitis and regeneration. These include direct and indirect effects on vasculature, impairment of neutrophil function, interference with collagen biosynthesis and maintenance, and altered immunoinammatory responses. Although some investigators have reported higher plaque levels in smokers (1, 85, 161163), others have not, and the observed differences were often very small (1). Likewise, the inuence of smoking on the bacterial ora is unclear. Zambon et al. (241) reported that smokers had higher levels of P . gingivalis and Bacteroides forsythus than nonsmokers with comparable clinical disease. Others, however have not observed microbial differences (165, 166, 215).

Poorly controlled diabetes inuences the control of microbial infections and the severity of periodontitis but has no clear inuence on the bacterial composition of dental plaque (Fig. 1, node 1.4)
Of all the systemic diseases that are relatively common, diabetes has emerged in recent years as the one with the strongest potential inuence on peri-

odontal diseases (67, 144). Various biological mechanisms may explain these effects (81). The relationship between diabetes and periodontal diseases is complicated and those complications are reected in the literature. Studies of insulin dependent diabetes (Type 1) in children found more gingivitis than healthy individuals but did not nd more periodontitis in the diabetics (37, 158). Although there are a few exceptions (147, 188), several studies have shown diabetes to be a signicant risk for more severe periodontitis in adults (44, 79, 147, 190, 205, 224). Unfortunately, longitudinal studies of periodontal therapy require so much compliance with an experimental protocol that the studies of diabetics inevitably select for diabetics who are relatively diligent in their glucose control. These individuals may also, by the nature of their appreciation of the role of their own responsibility for their health, tend to have good oral hygiene. In well-controlled diabetics, clinical responses to both surgical and nonsurgical periodontal therapy produced similar results to those observed in non-diabetics (222, 233). In general, poorly controlled diabetes appears to be associated with an increased risk of loss of attachment and loss of bone. Well-controlled diabetics do not appear to be at an increased risk for periodontitis. Although there are no direct data, other than individual case reports, on the response of diabetics to regenerative therapy, this factor should be explicitly considered when considering surgical therapy for individual patients. Microbial defense mechanisms are known to be impaired in diabetics (196), and the susceptibility to infection appears to be related to hyperglycemia and the degree of glucose control (128, 214). Diabetics are at particular risk for infections associated with wounds or surgery (48, 97, 112). Mean blood glucose level through the rst 2 days after open heart surgery was a signicant independent predictor of deep wound infection, and clinical protocols designed to manage postoperative glucose levels achieved a signicant reduction in infections (212, 242). However, similar periodontal pathogens have been reported in periodontitis sites in both diabetic (119, 123, 195, 239) and non-diabetic patients (74). In addition, the subgingival microbiota in diseased sites in diabetics appears to be unrelated to metabolic control (195, 223). It therefore seems reasonable to conclude that: O diabetes does not directly alter the plaque composition;

28

Outcome of therapy for osseous lesions

O diabetes is likely to alter the tissue response to the bacteria; O diabetes is likely to increase the deep wound infections that may result from any surgical procedure; and O the degree of hyperglycemia is likely to account for the increased susceptibility to infections.

Aging alters resistance to microbial infections (Fig. 1, node 1.6)

In almost all epidemiological studies of periodontitis or studies that evaluate multiple risk factors in a broad population group, plaque and age are the most consistent associations with disease (19). It is unclear, however, whether the statistical associations with aging are due to merely cumulative effects of a chronic disease or represent an alteration in the host response as a result of the biology of aging. It should also be emphasized that, in questions of the role of aging, one must distinguish intrinsic effects of aging from the effects of several diseases, nutritional deciencies, and medications that may be enriched in the elderly population. Mechanistically, there are data to support the conclusions that aging is associated with a decline in host protective mechanisms against bacterial infections and an impaired healing response. The evidence for an aging effect, by itself, on decline in immune function is documented in the literature (34, 73). Decreased cell-mediated immunity has been reported in elderly people, and some impairments in immunoregulatory aspects of T-cell function appear to be present. For example, it is well established that elderly people develop a less consistent antibody response to immunizations. In particular, decreased levels of soluble interleukin-2 receptors and interferon alpha have been reported along with decreased CD8 cells (210). In addition, as more is learned about the closely integrated activities of the immune system and steroid hormones, it is to be expected that signicant immune changes will occur as steroid levels in the body decline with age. Since bacterial contamination appears to have a major inuence on success of regenerative procedure, aging may play a role in success of regenerative procedures by increasing the likelihood of bacterial contamination.

Genetic factors associated with different clinical types of periodontitis inuence the plaque composition (Fig. 1, node 1.5)
In the past few years a variety of genetic factors have been identied that alter the immunoinammatory responses, and therefore may alter the control of bacterial infections. The hosts control of bacteria in the periodontal area is primarily determined by polymorphonuclear neutrophils and specic antibody (83). Specic antibody forms a bridge between the target microorganism and polymorphonuclear neutrophils and thereby, makes the polymorphonuclear neutrophils more efcient in removing the bacterial cells. The effectiveness of antibody protection against A. actinomycetemcomitans is a function of the serum level and avidity of immunoglobulin G2 (IgG2) and of the polymorphonuclear neutrophil receptors (FcgIIR) that bind the IgG2 antibody (113, 197). In early-onset periodontitis, signicant variation has been found in the titers of IgG2, and lower levels of IgG2 have been associated with a more generalized spread of the bacterial infection and clinical disease (59). Studies have shown that most of the variance in IgG2 levels is genetically determined (120, 121). In addition, investigators have shown that a genetic variation in the FcgII receptor on the polymorphonuclear neutrophils inuences how efciently the A. actinomycetemcomitans cells are phagocytosed by the polymorphonuclear neutrophils (234236). Thus, at least two genetically controlled factors have the potential to alter the bacterial composition of the plaque in some individuals. There are several reports (39, 104, 191, 211, 238) of the use of guided tissue regeneration procedures in early-onset periodontitis cases. Although the case reports have been generally favorable, at least one controlled study (39) showed no advantage for guided tissue regeneration approaches over surgical debridement in early-onset disease.

Innate wound-healing potential (Fig. 1, node 2.0)

The clinical outcome of therapy for osseous defects is predicated on the concept that certain aspects of the wound-healing process can be controlled to achieve a specic relationship among various tissues. Since wound healing is a structured sequence of chemotactic and mitogenic signals and responses (21, 63, 96, 124), any alterations in the growth factors, cytokines, and other mediators that

29

Kornman & Robertson

provide those signals have the potential to inuence the outcomes of therapies for osseous defects. No direct data are currently available relative to specic alterations in wound healing mechanisms and the outcomes of regeneration procedures. Such studies are possible in animal models, and substantial literature is evolving on the role of specic growth factors in wound healing.

Genetic factors inuence mediators of inammation (Fig. 1, node 2.1)

Various genetic factors inuence some aspect of the inammatory process. A recent report indicates that a specic genetic factor in the genes for interleukin1 is associated with: 1) increased levels of the inammatory cytokine interleukin-1 and 2) more inammation and 3) more severe periodontitis (100, 101). Data indicate that there is a less favorable guided tissue regeneration response in sites with inammation (117). It will be interesting to evaluate the clinical responses to regenerative therapy in patients who are genetically programmed to have a more robust inammatory response.

matory response in diabetics, which then leads to a cascade of other growth factors that are involved in the wound-healing process (219). Although no direct data are available, it is very likely that diabetics who are not optimally controlled will have an altered healing response with procedures designed to treat osseous defects. The magnitude or clinical signicance of this inuence is not known. Given current knowledge on the biochemical mechanisms involved in diabetes, it is likely that the clinical signicance of the disease relative to impact on the healing response will be a function of the control of the glucose metabolism. It seems reasonable therefore to conclude the following: O Although no direct data are available, diabetics with less than optimal glucose control should theoretically be at increased risk for failure with regenerative procedures. O The risk of failure in diabetics is likely to be related to the stability of long-term control of glucose metabolism. O One component of the increased risk may be an increased microbial challenge. See above. O One component of the increased risk may be a delayed wound healing response that is most likely the result of poor control of glucose metabolism on the inammatory process. Improved metabolic control is currently the only practical approach to managing this risk factor. O There are currently no data to quantify the inuence of diabetes on the success of regeneration.

Diabetes inuences wound repair and healing (Fig. 1, node 2.2)

Impaired wound healing and repair is a well-accepted consequence of diabetes, and in recent years investigators have described some of the biochemical characteristics of delayed wound healing in diabetics. Local growth factors that inuence cell migration, proliferation, and phenotypic expression appear to explain much of the delay in wound healing in diabetics, at least in animal models (145). For example, broblast mitogens including the BB homodimer of platelet-derived growth factor plus insulin-like growth factor or basic broblast growth factor plus insulin-like growth factor synergistically enhance wound closure in the genetically diabetic mouse model. In addition, when platelet-derived growth factor-BB was combined with the keratinocyte mitogen transforming growth factor a, wound closure in the diabetic mouse approached the closure rate observed in non-diabetic controls (15, 16). Some of these growth factors, when added exogenously, have also been shown to restore the local tissue inam-

Smoking interferes with wound healing in various areas of the body (Fig. 1, node 2.3)
Recent reviews have discussed the effects of smoking on healing in general (51) after plastic surgery and orthopedic surgery procedures (25, 102, 135). The strength of smoking as a determinant of wound healing was reported by Rees et al. (173) in a retrospective analysis of 1186 consecutive face lift surgeries. Although 25% of their patients were smokers, 80% of those with a history of ap sloughing smoked at least 1 pack per day. Various experimental models have assessed the inuence of smoking on specic components of the wound-healing process (24). In an experimental

30

Outcome of therapy for osseous lesions

model in rabbits, nicotine was shown to interfere with various aspects of wound healing between days 6 to 10. The authors (134) suggested the effects may be due to alterations in 3 critical systems, the inammatory process, epithelialization and vascularization. In experimental models of microvascular healing and proliferation, smoking was found to signicantly delay endothelial cell migration (69). In addition, polymorphonuclear neutrophil migration, an essential component in the wound-healing response, was inhibited in the gingiva of dogs by products from tobacco smoke (93). Associations between smoking and adverse surgical outcomes have been reported in several systems: for example, smoking increased the incidence of localized osteitis following third molar extraction (217), and the cosmetic results, including size and color of skin incision scars, were substantially worse in smokers (206). The effect of smoking on the outcomes of regenerative procedures is discussed above. The following conclusions appear to be reasonable at this time: O Smoking is a strong risk factor for adverse outcomes of regenerative therapy. O Patients who have stopped smoking appear to have no greater risk for adverse outcomes than patients who have never smoked. O There are reasons to believe that cessation of smoking prior to regenerative therapy and for at least the post-surgical healing phase may be benecial to wound healing; however, there are no data relative to how a return to smoking may inuence the long-term prognosis.

growth factor and reduced levels or quality of collagen are characteristic of healing wounds in older individuals (4, 5, 175). It is difcult to identify a specic age that may represent an increased risk for regenerative procedures, but it seems appropriate in a multi-risk model to assume that there is a somewhat greater risk for problems in patients over the age of 65. Whether this increased risk is sufcient to make a clinical difference remains to be determined. In a study of the factors associated with guided tissue regeneration success (117), the clinical responses were dichotomized into a younger group (age 27 to 44 years) and an older group (age 48 to 66 years). The outcome for these two age ranges were essentially identical. Whether this lack of an age effect applies to individuals over the age of 65 remains to be determined.

Site characteristics (Fig. 1, node 3.0)

When the long-term response of regenerative therapy was determined for multiple sites in the same patient (32), some sites appeared to respond concordantly, suggesting patient level factors such as smoking dominated the results. In other patients, however, the responses of multiple sites in the same patient were very discordant, suggesting that individual site characteristics dominated the response. Similar observations have been made in retrospective analyses of the factors that predict response to periodontal therapy (125127).

Aging inuences specic components of the woundhealing process (Fig. 1, node 2.4)
Although there has long been a general impression that aging is associated with a compromised woundhealing process, some of the potential mechanisms for such an effect have been identied only recently (2, 9, 38, 155, 204, 228). The aging effect appears to be especially prominent in surgical wounds in which there is some early ischemia. Ischemic wounds in older animals have signicantly lower numbers of mononuclear cells inltrating the wounds and display a reduced strength, as compared to younger animals (56, 237). Lower levels of platelet-derived

Pulpal status has been associated with adverse periodontal wound healing under certain conditions (Fig. 1, node 3.1)
Understanding the effect of pulpal conditions on repair or regeneration of periodontal osseous lesions becomes more critical as an increasing percentage of the population retain most of their teeth for an increasingly longer lifetime. Recent prevalence studies in three adult populations (Table 1) estimate that the average percentage of teeth with periapical disease is about 34% and with root llings is about 39%. About 50% of patients included in a survey of endodontic status in a German population (232) showed at least one tooth with a root lling or signs

31

Kornman & Robertson

Table 1. Recent studies showing prevalence of teeth with periapical periodontitis and root lling as a percentage of subjects total teeth
Reference Weiger et al. (232) Buckley & Spngberg (18) Imfeld (82) Odesjo et al. (143) Population Germany United States Switzerland Sweden Age range 1980 2081 66 2060 Periapical teeth 3.0 4.1 8.4 2.9 Root-lled teeth 2.7 5.5 20.3 8.6

Source: Adapted from Weiger et al. (232) and Buckley & Spngberg (18).

of pulpal disease. Endodontic treatment was observed more often among maxillary (60%) than mandibular teeth, and the frequency of root-lled teeth was highest for maxillary anterior (26%) and maxillary premolar (21%) teeth and lowest for mandibular premolar (10%) and incisor (2%) teeth. This distribution is consistent with endodontic treatment frequencies for all teeth (Fig. 2) reported by Buckley & ngberg (18). In general, the prevalence of both Spa endodontic treatment and pulpal disease increased dramatically with age. Among a sample of 66-yearold residents of Zurich, 78% had at least one endodontically treated tooth and 20% of all teeth were root lled (82). Pulpal conditions that may impair healing of periodontal osseous defects were recently reviewed by Chen et al. (26), and are based primarily on passage of microorganisms or microbial products, inammatory mediators associated with pulpal disease or toxic substances associated with endodontic treatment from the pulp to periodontal tissues through lateral canals and patent dentinal tubules. Support for the potential of these pathways to adversely affect the periodontium accrues from studies demonstrating the similarity of microbial populations in pulpal and periodontal infections (95, 98, 220), clinical and histological examples of periodontal destruction associated with untreated accessory root canals containing bacteria and necrotic debris (8) and the possible toxic effects of medicaments and sealers used in endodontic treatment (3, 45). The potential of pulpal conditions to affect periodontal tissues may depend on the integrity and previous disease history of the periodontium. For teeth with a normal periodontium, there is little evidence that pulpal disease or endodontic treatment are principal etiological factors in the initiation of periodontitis. Harrington (75) observes that the presence of lateral canals in the coronal one-third of the root is infrequent (157), a condition that is not consistent with the crestal initiation and subsequent apical extension of periodontitis. Rather, he suggests that true

combined pulpal-periodontal lesions occur primarily when independent periodontal and periapical or lateral lesions are present and eventually communicate. Harrington argues that this causative independence of pulpal and periodontal diseases in the initially normal periodontium mandates a careful diagnosis to dene lesions of pulpal origin. These include acute lesions, radiolucent lesions in which the gingival sulcus is intact, and sinus tract lesions, for which endodontic therapy alone will result in rapid periodontal repair. However, for patients with a history of periodontitis, Jansson et al. (86, 87) conclude that teeth with coexisting periodontal and pulpal disease show deeper probing depths, more advanced radiographic attachment loss and a greater frequency of angular defects, than periodontally involved teeth without pulpal disease. Moreover, during an observation period of at least 3 years in a population with periodontitis, teeth with progressing periapical pathology showed three times the rate of proximal bone loss than teeth with no signs of periapical pathology or teeth with periapical destruction that subsided (88). The conclusions of studies that assess the inuence of pulpal condition on periodontal wound healing (Table 2) also appear to depend on the initial integrity of the periodontium. Studies are grouped by those in which the experimental model examined reattachment, wherein periodontal structures have not been affected by disease and healing can occur by a reunion of epithelium and connective tissues with a non-altered root surface, versus models that examined new attachment, wherein periodontal tissues damaged by disease are repaired but the new union of epithelium and connective tissue with a root surface may not duplicate the original attachment apparatus. To compare the extent of reattachment in teeth with vital, extirpated and root-lled n (76) made an experimental cavity in canals, Hellde the facial aspect of roots in humans at an apical distance remote from any periodontal disease process, whereas Diem et al. (40) and Perlmutter et al. (154)

32

Outcome of therapy for osseous lesions

Fig. 2. Endodontic treatment frequencies for all teeth. Source: adapted from Buckley & Spngberg (18).

surgically exposed periodontally healthy facial root surfaces in primates. The extent and histological pattern of reattachment was similar, irrespective of pulpal status, and all three studies concluded that reunion of periodontal tissues with an initially healthy root surface was not inuenced by the condition of the pulp. Conversely, assessments of new attachment in patients treated for periodontitis (42, 43, 86, 87, 194) and in dogs with experimentally induced periodontitis (105) concluded that periapical pathosis or root canal therapy adversely inuenced new attachment in osseous defects. Present evidence suggests that pulpal disease, in general, and subsequent endodontic treatment, in particular, may impair efforts to achieve new attachment in patients with a history of periodontitis. The hypothesis is consistent with early histological observations of Morris (132, 133), who used a surgical detachment model that probably represents a combination of reattachment and new attachment, and who observed histological resolution of the surgical wounds in 10 of 11 vital teeth (132) but only in 5 of 17 non-vital teeth (133). Moreover, the evidence supports clinical concerns of Prichard (168) who warned that successful therapy for intrabony defects might be compromised by root canal llings. However, in addition to problems of experimental ap-

proach, group size and relatively small clinical differences in defect resolution between vital and nonvital teeth, available studies do not address the pathways of impaired healing or the effect of pulpal condition on approaches to guided tissue regeneration.

A role for occlusion in the outcomes of regenerative procedures has not been established (Fig. 1, node 3.2)
In the Proceedings of the 1966 World Workshop in Periodontics, Waerhaug (229) concluded that studies from the turn of the century to that time gave little support to any major role for abnormal occlusal function in the development of gingival anatomic defects or gingival inammation and initiation of periodontal pocket formation or alveolar bone destruction associated with periodontitis. Based on this conclusion, he suggested that the justication for including occlusal equilibration and splinting as part of periodontal therapy required further investigation. Reviews of investigations on abnormal occlusion during the ensuing 10 years by Ranney (172) and Robinson (181) strengthened the hypothesis

33

Kornman & Robertson

Table 2. Case studies comparing pulpal condition with periodontal healing

Reference model n et al. (76) Hellde Reattachment Human Pulpal condition 3 groups: vital, nonvital and root cavity lled Design Flap; wound cavity through bone into root surface with bur; healing7593 days; biopsy by block section Endodontic treatment; ap; notch landmarks placed; surgically remove bone; healing91 days; biopsy by block section Endodontic treatment; ap; notch landmarks placed with diamond wheel; surgically remove bone; healing 2365 days; biopsy by block section Freeze-dried bone allografts placed in periodontal osseous defects. Bone regeneration evaluated by surgical re-entry 1 year after grafting Probing depths measured before and after scaling and root planing; healing436 months Results Healing with new cementum in 22/31 vital; 16/21 nonvital and 10/17 root cavity lled New cementum formed over dentin in 20/22 teeth irrespective of pulp status Conclusions Tooth vitality of limited importance for root surface healing

Diem et al. (40) Reattachment Rhesus monkeys

3 groups: vital, extirpated and root cavity lled

Healing of attachment apparatus occurred on pulpless teeth denuded of cementum regardless of status of root canal chamber

Perlmutter et al. (154) Reattachment Baboons

3 groups: vital, extirpated and root cavity lled

Usual histological Vitality of tooth did not healing patterns inuence reattachment observed in all groups; new cementum formed regardless of pulpal status Nonobturated Endodontically 165/254 (65%) showed obturated teeth may complete or 50% impair graft success bone ll Root cavity lled 6/18 (33%) showed complete or 50% bone ll Multiple regression analysis showed impaired mean pocket depth reduction in periapically positive compared with periapically negative teeth (mean difference 0.51.0 mm) Histometric measurements expressed as a percentage of total defect length were signicantly less for new bone, cementum and connective tissue in root cavity lled groups than vital groups Teeth with periapical lesions show impaired response to periodontal therapy

Sanders et al. (194) New attachment (bone regeneration in human osseous defects)

2 groups: root cavity lled and nonobturated (pulpal status unknown)

Jansson et al. (86, 87) Ehnevid et al. (42, 43) New attachment (probing depth reduction in humans)

Radiographic evaluation of negative or positive periapical destruction

Lima et al. (105) New attachment (healing of experimental periodontitis in dogs)

4 groups: vital, scale and root plane; vital, ap surgery; root cavity lled concurrent with surgery; and root cavity lled 3 weeks after surgery

Intrabony defects created surgically; ligatures placed; periodontal therapy; healing7 weeks; biopsy by block section

Root canal therapy performed simultaneously or shortly after ap therapy will impair new bone, cementum and connective tissue healing

that occlusal overload does not initiate gingivitis or periodontitis, supported a possible role for occlusal trauma in accelerating the progression of existing periodontitis, and noted new information suggesting minimal occlusal inuence on recurrence of treated periodontitis. Much of this progress was grounded in studies on the inuence of trauma from occlusion on experimental periodontitis in beagle dog (107, 108) and squirrel monkey (159, 160) models. Discussions associated with the review by Hoag (77) in the subsequent Proceedings of the World Workshop in Clinical Periodontics reect a renewed interest in the effect of tooth mobility, irrespective of cause, on the response to periodontal therapy. Such discussions mirrored human studies showing that attachment gains after periodontal therapy were

greater in nonmobile than mobile teeth (49). Some additional evidence endorsing tooth hypermobility as a negative factor in repair or regeneration of periodontal osseous defects is discussed by Garrett (54) and Gher (57) in the proceedings of the 1996 World Workshop in Periodontics. However, both authors conclude that the role of abnormal occlusion and associated mobility in treatment of periodontitis remain unresolved. While controversy endures about occlusion as a risk factor in periodontal therapy (216), reviews of almost a century of research have established many areas of consensus. Occlusal forces that exceed physiological thresholds, whether a function of force magnitude, duration or direction, do not initiate gingivitis or periodontitis but can result in bone re-

34

Outcome of therapy for osseous lesions

modeling and tooth mobility. Occlusal forces of sufcient magnitude to cause severe or increasing tooth hypermobility may accelerate attachment loss in existing, plaque-induced periodontitis and, in addition, may interfere with repair or regeneration of connective tissue attachment lost to periodontitis. Occlusal equilibration or other methods of achieving tooth stabilization are not appropriate to prevent initiation or recurrence of periodontitis, but they may be indicated in hypermobile teeth to mechanically favor periodontal regenerative techniques. However, since the inuence of mobility on periodontal regeneration remains undened, procedural approaches to such tooth stabilization should be primarily noninvasive and effect minimal loss of tooth structure.

Defect morphology and tooth anatomy appear to inuence the outcome of regenerative therapy (Fig. 1, node 3.3)
The prevailing hypothesis explaining anatomical characteristics of periodontal osseous defects is based on evidence that the microbial mass colonizing a root surface will induce bone resorption to an apical or lateral limit, beyond which bone resorption either ceases or is matched by bone production (53, 230). Page & Schroeder (148) postulate that this microbial radius of effectiveness combined with highly variable dimensions of bone adjacent to infected root surfaces results in the wide range of intraosseous and furcation defects associated with periodontitis. Thus, intraosseous defects would occur adjacent to infected root surfaces where the distance from the cribriform plate to either the external cortex or neighboring root surface exceeds the radius of effectiveness. An estimate of this radius is about 2.5 mm, although the concept is more important than the actual radius distance, which may depend on tolerance of the host, location and pathogenic potential of the plaque biolm, pre-existing anatomical abnormalities, abscess formation, or frank bacterial invasion of periodontal tissues (198). Nevertheless, Tal (218) observed very few intraosseous defects where interdental distances were less than 2.6 mm in 81 patients treated surgically for periodontitis. Given considerable morphological variation exhibited by the periodontium (189), the hypothesis predicts loss of all bone opposing infected facial root surfaces with a thin alveolar hous-

ing, circumscribed intraosseous defects contiguous to infected proximal root surfaces bounded by edentulous areas and the wide range of vertical, angular, hemiseptal and furcation defects between these extremes. These widely ranging osseous defect characteristics have long been related to success of regenerative therapy (54), particularly the number of associated bony walls (58, 167, 182, 184) and overall defect depth (176). More recent studies of defect conguration as a factor in the response of intraosseous defects to guided tissue regeneration have both conrmed and challenged these beliefs. In a retrospective analysis of 26 proximal defects treated with ap surgery and expanded polytetrauoroethylene barrier membranes, Selvig et al. (201) concluded that the extent of crestal involvement, circumference, number of tooth walls involved, and wall form in the fundus of the defect did not inuence the healing response. Attachment gain and bone ll were positively correlated with the depth of the 3-walled intraosseous component of the defect. A series of studies focused on factors affecting healing of intraosseous defects treated by guided tissue regeneration (225227), also identied increased total depth of the intraosseous component of the defect as well as decreased radiographic width of the defect angle as important positive correlates of regeneration. It was suggested that the decreased amount of regeneration associated with an increased radiographic defect angle between the root surface and defect wall may reect space loss and clot disturbance caused by postoperative collapse of the membrane, the greater distances required for cellular repopulation of the wound or an enhanced susceptibility to oral environmental factors leading to incomplete bone ll. These latter oral environmental factors, including mechanical trauma and infection, are also proposed as primary reasons for incomplete ll of the most supercial portion of the defect. Enamel projections, bifurcational ridges, lingual grooves, irregularities in root morphology, and other factors related to tooth anatomy have been implicated in the causation of periodontal disease, primarily because they favor plaque accumulation (90). Indeed, Hou & Tsai (78) recently reported signicantly higher mean values for plaque accumulation, gingival inammation, probing depth and clinical attachment loss in furcation-involved molars with an intermediate bifurcational ridge and cervical enamel projection than furcation-involved molars without these morphological features. It is reasonable to expect that such factors may also adversely affect the

35

Kornman & Robertson

success of regenerative procedures (177), since the presence of plaque (117) and related periodontal inammation (225, 226) and the inability to maintain high levels of oral hygiene (30) endanger a positive outcome of guided tissue regeneration.

Surgical procedure (Fig. 1, node 4.0)

With surgical procedures, some component of the variability in outcomes, may be attributed to the surgeon. Although these individual operator differences are difcult to dene from literature reports, careful analysis of the actions of a specic practitioner may reveal actual procedures, such as postoperative care, that inuence bacterial contamination. Certainly, one of the characteristics of an experienced clinician is the matching of specic procedures to the appropriate patients and the appropriate sites. Substantial components of an individuals experience with a surgical procedure therefore may be attributed to factors (Fig. 1) that inuence bacterial contamination, innate wound healing potential, and site selection.

Root surface preparation (Fig. 1, node 4.1)

Clinical observations, epidemiological surveys and controlled therapeutic trials have long identied preparation of the root surface as an essential element in the success of periodontal treatment, regardless of therapeutic approach (28, 41, 92). Indeed, re-establishment of a connective tissue attachment to the root surface is the dening event for true periodontal regeneration. However, periodontitis causes such profound structural, compositional and cytotoxic changes in the root surface (14, 103) and creates an environment so unfavorable for constituting a new attachment apparatus that conventional periodontal therapy results primarily in repair, with epithelium lining the damaged root surface (22, 151). Thus, a major challenge to regenerative efforts is alteration of the root surface to neutralize cytotoxic residuum and encourage cell-mediated connective tissue proliferation. Demineralizing agents, including citric acid and tetracycline, have been proposed to remove smear layers remaining after mechanical debridement, to expose collagen bers or to detoxify the root surface. In general, studies that examined the use of citric

acid and other root-conditioning agents to enhance gingival connective tissue attachment have not demonstrated consistent clinical or histological advantages (33, 52, 54, 122, 142). Application of regulatory polypeptides and glycoproteins, bronectins and a variety of collagen preparations to the root surface or adjacent lesion site has great potential in orchestrating cell-mediated regeneration (114, 115, 179, 186, 187), but clear therapeutic protocols have not been established. In the absence of chemical and biological approaches, mechanical scaling and root planing remains the principal means of root surface decontamination. The benet of root planing appears to accrue from removing subgingival plaque and calculus and mechanically disrupting the remaining subgingival ora. Since an established subgingival microbial biolm is protected to a great extent from both intrinsic host defense effectors and extrinsic chemotherapeutic agents, physical disruption remains central to any periodontal therapy (150). In addition, some evidence suggests that removing calculus and supercial cementum may also eliminate bacterial toxins incorporated into the root surface (146, 153). Many studies have shown that root planing, combined with excellent plaque control, are effective in resolving both gingivitis and periodontitis, and long-term trials that compare root planing alone and combined with a variety of surgical procedures suggest that debridement of the root surface accounts for a major part of reported therapeutic success (6, 7, 84, 89, 90, 109, 156). Less clear is the clinical endpoint required to achieve a favorable root surface environment in a particular site or particular host. For example, while one accepted endpoint is complete removal of all calculus from the root surface, a number of investigations have shown that about 50% of all surfaces retained some residual calculus even after extended scaling or root planing (17, 20, 169, 174, 180, 203). An explanation of this residual calculus paradox (180) is that while total elimination of causative factors is the appropriate treatment goal, reduction of plaque and calculus to threshold levels that are acceptable to a particular host will control the infectious process and improve clinical signs of inammation. It is important to note that thin calculus veneers may be compatible with resolution of periodontal inammation and formation of a long junctional epithelial attachment to the root surface (111) but may also act as a physical and biological barrier, which prevents new attachment or regeneration of a functional attachment apparatus (94).

36

Outcome of therapy for osseous lesions

Other components of the surgical procedure

The specic devices and surgical approaches that may be employed in regenerative procedures are discussed by others in this volume. Operator skill certainly may differ relative to tissue management, attention to blood supply and other factors that inuence some component of the healing response. Those aspects of skill are difcult to assess and to quantify. Some components of operator skill, as discussed above, most likely relate to patient and site selection and post-operative management. Those aspects of skill are discussed above in relation to factors that inuence bacterial contamination, innate healing potential and site characteristics.

Conclusion
After surgical procedures are shown to be benecial, studies must begin to identify specic factors that contribute to the variability in clinical outcomes. Several studies are available that have specically identied some of the major inuences on variability of responses to therapies designed to treat osseous defects by means of regeneration. Other data relative to periodontal disease or relative to surgical procedures, in general, have suggested other potential inuences on regenerative outcomes. It now appears that regenerative outcomes in systemically healthy individuals are primarily inuenced by plaque control, smoking and various local site characteristics.

References
1. Ah MKB, Johnson GK, Kaldahl WB, Patil KD, Kalkwarf KL. The effect of smoking on the response to periodontal therapy. J Clin Periodontol 1994: 21: 9197. 2. Amler MH. Age factor in human alveolar bone repair. J Oral Implantol 1993: 19: 138142. 3. Andreasen JO. The effect of pulp extirpation or root canal treatment on periodontal healing after replantation of permanent incisors in monkeys. J Endod 1981: 7: 245 252. 4. Ashcroft GS, Horan MA, Ferguson MW. The effects of aging on wound healing: immunolocalisation of growth factors and their receptors in a murine incisional model. J Anat 1997: 190(part 3): 351365. 5. Ashcroft GS, Horan MA, Ferguson MW. Aging is associated with reduced deposition of specic extracellular matrix components, an upregulation of angiogenesis, and an altered inammatory response in a murine incisional wound healing model. J Invest Dermatol 1997: 108: 430 437.

6. Axelsson P, Lindhe J. The signicance of maintenance care in the treatment of periodontal disease. J Clin Periodontol 1981: 8: 281294. us R, Egelberg J. Four-year observations 7. Badersten A, Nilve of basic periodontal therapy. J Clin Periodontol 1987: 14: 438444. 8. Barkhordar RA, Stewart GG. The potential of periodontal pocket formation associated with untreated accessory root canals. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1990: 70: 769772. 9. Beck LS, DeGuzman L, Lee WP, Xu Y, Siegel MW, Amento EP. One systemic administration of transforming growth factor-beta 1 reverses age- or glucocorticoid-impaired wound healing. J Clin Invest 1993: 92: 28412849. m J, Floderus-Myrhed B. Co-twin control study of 10. Bergstro the relationship between smoking and some periodontal disease factors. Community Dent Oral Epidemiol 1983: 11: 113116. 11. Bergstro m J, Eliasson S. Cigarette smoking and alveolar bone height in subjects with a high standard of oral hygiene. J Clin Periodontol 1987: 14: 466469. m J, Eliasson S, Preber H. Cigarette smoking and 12. Bergstro periodontal bone loss. J Periodontol 1991: 62: 242246. 13. Bergstro m J, Preber H. Tobacco use as a risk factor. J Periodontol 1994: 65(suppl): 545550. 14. Bosshardt DD, Selvig KA. Dental cementum: the dynamic tissue covering of the root. Periodontol 2000 1997: 13: 41 75. 15. Brown RL, Breeden MP, Greenhalgh DG. PDGF and TGFalpha act synergistically to improve wound healing in the genetically diabetic mouse. J Surg Res 1994: 56: 562570. 16. Brown DL, Dao WW, Greenhalgh DG. Apoptosis downregulates inammation under the advancing epithelial wound edge: delayed patterns in diabetes and improvement with topical growth factors. Surgery 1997: 121: 372 380. 17. Buchanan SA, Robertson PB. Calculus removal by scaling and root planing with an without surgical access. J Periodontol 1987: 58: 159163. 18. Buckley M, Spngberg LSW. The prevalence and technical quality of endodontic treatment in an American subpopulation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995: 79: 92100. 19. Burt BA. Periodontitis and aging: reviewing recent evidence. J Am Dent Assoc 1994: 125: 273279. 20. Caffesse RG, Sweeney PL, Smith BA. Scaling and root planing with and without periodontal ap surgery. J Clin Periodontol 1986: 13: 205210. ones CR. Polypeptide growth factors 21. Caffesse RG, Quin and attachment proteins in periodontal wound healing and regeneration. Periodontol 2000 1993: 1: 6979. 22. Caton J, Nyman S, Zander H. Histometric evaluation of periodontal surgery. II. Connective tissue attachment levels after four regenerative procedures. J Clin Periodontol 1980: 7: 224231. 23. Caton JG, Greenstein G. Factors related to periodontal regeneration. Periodontol 2000 1993: 1: 915. 24. Chamson A, Frey J, Hivert M. Effects of tobacco smoke extracts on collagen biosynthesis by broblast cell cultures. J Toxicol Environ Health 1982: 9: 921932. 25. Chang LD, Buncke G, Slezak S, Buncke HJ. Cigarette smoking, plastic surgery, and microsurgery. J Reconstr Surg 1996: 12: 467474.

37

Kornman & Robertson

26. Chen SW, Wang HL, Glickman GN. The inuence of endodontic treatment upon periodontal wound healing. J Clin Periodontol 1997: 24: 449456. 27. Chen YT, Wang HL, Lopatin DE, ONeal R, MacNeil RL. Bacterial adherence to guided tissue regeneration barrier membranes exposed to the oral environment. J Periodontol 1997: 68: 172179. 28. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol 1996: 1: 443490. 29. Cortellini P, Pini Prato G, Tonetti MS. Periodontal regeneration of human intrabony defects. I. Clinical measures. J Periodontol 1993: 64: 254260. 30. Cortellini P, Pini-Prato G, Tonetti M. Periodontal regeneration of human infrabony defects. V. Effect of oral hygiene on long-term stability. J Clin Periodontol 1994: 21: 606 610. 31. Cortellini P, Bowers GM. Periodontal regeneration of intrabony defects: an evidence-based treatment approach. Int J Periodontics Restorative Dent 1995: 15: 128145. 32. Cortellini P, Paolo G, Prato P, Tonetti MS. Long-term stability of clinical attachment following guided tissue regeneration and conventional therapy. J Clin Periodontol 1996: 23: 106111. us R, Egelberg J, Selvig KA. The 33. Crigger M, Bogle G, Nilve effect of topical citric acid application on the healing of experimental furcation defects in dogs. J Periodontal Res 1978: 13: 538549. 34. Daynes RA, Araneo BA, Hennebold J, Enioutina E, Mu HH. Steroids as regulators of the mammalian immune response. J Invest Dermatol 1995: 105(suppl): 14S19S. 35. Demolon IA, Persson GR, Moncia BJ, Johnson RH, Ammons WF. Effect of antibiotic treatment on clinical conditions and bacterial growth with gided tissue regeneration. J Periodontol 1993: 64: 609616. 36. Demolon IA, Persson GR, Ammons WF, Johnson RH. Effect of antibiotic treatment on clinical conditions with guided tissue regeneration: one year results. J Periodontol 1994: 65: 713717. C, Robert JJ, Brion M. 37. de Pommereau V, Dargent-Pare Periodontal status in insulin-dependent diabetic adolescents. J Clin Periodontol 1992: 19: 628832. 38. Desai H. Aging and wounds. 2. Healing in old age. J Wound Care 1997: 6: 237239. 39. DiBattista P, Bissada NF, Ricchetti PA.. Comparative effectiveness of various regenerative modalities for the treatment of localized juvenile periodontitis. J Periodontol 1995: 66: 673678. 40. Diem CR, Bowers GM, Ferrigno PD, Fedi PF. Regeneration of the attachment apparatus on pulpless teeth denuded of cementum in the rhesus monkey. J Periodontol 1974: 45: 1822. 41. Drisko CL, Killoy WJ. Scaling and root planing: removal of calculus and subgingival organisms. Curr Opin Dent 1991: 1: 7480. 42. Ehnevid H, Jansson L, Lindskog S, Blomlo f L. Periodontal healing in teeth with periapical lesions. A clinical retrospective study. J Clin Periodontol 1993: 20: 254258. f LB. Peri43. Ehnevid H, Jansson LE, Linskog SV, Blomlo odontal healing in relation to radiographic attachment and endodontic infection. J Periodontol 1993: 64: 1199 1204. 44. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol 1991: 62: 123131. 45. Erausquin J, Muruzabel M. Necrosis of cementum induced by root canal treatments in the molar of rats. Arch Oral Biol 1967: 12: 11231132. 46. Falk H, Laurell L, Ravald N, Teiwik A, Persson R. Guided tissue regeneration therapy of 203 consecutively treated intrabony defects using a bioabsorbable matrix barrier. Clinical and radiographic ndings. J Periodontol 1997: 68: 571581. 47. Feldman RS, Bravacos JS, Rose CL. Association between smoking different tobacco products and periodontal disease indexes. J Periodontol 1983: 54: 481487. 48. File TM Jr, Tan JS. Infectious complications in diabetic patients. Curr Ther Endocrinol Metab 1997: 6: 491495. 49. Fleszar TJ, Knowles JW, Morrison EC, Burgett FG, Nissle RR, Ramfjord SP. Tooth mobility and periodontal therapy. J Clin Periodontol 1980: 7: 495505. 50. Frandsen EV, Sander L, Arnbjerg D, Theilade E. Effect of local metronidazol on periodontal healing following guided tissue regeneration. Microbiological ndings. J Periodontol 1994: 65: 921928. 51. Frick WG, Seals RR Jr. Smoking and wound healing: a review. Tex Dent J 1994: June: 2123. 52. Gantes B, Martin M, Garrett S, Egelberg J. Treatment of periodontal furcation defects. II. Bone regeneration in mandibular class II defects. J Clin Periodontol 1988: 15: 232239. 53. Garant PR, Cho MI. Histophathogenesis of spontaneous periodontal disease in conventional rats. I. Histometric and histologic study. J Periodontal Res 1979: 14: 297 309. 54. Garrett S. Periodontal regeneration around natural teeth. Ann Periodontol 1996: 1: 621666. 55. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996: 67(suppl): 10411049. 56. Gerstein AD, Phillips TJ, Rogers GS, Gilchrest BA. Wound healing and aging. Dermatol Clin 1993: 11: 749757. 57. Gher ME. Non-surgical pocket therapy: dental occlusion. Ann Periodontol 1996: 1: 567580. 58. Goldman H, Cohen DW. The infrabony pocket: classication and treatment. J Periodontol 1958: 29: 272291. 59. Gonsolley JC, Burmeister JA, Tew JG, Best AM, Ranny RR. Relationship of serum antibody to attachment level patterns in young adults with juvenile periodontitis or generalized severe periodontitis. J Periodontal Res 1987: 58: 314320. 60. Gonzalez YM, De Nardin A, Grossi SG, Machtei EE, Genco RJ, De Nardin E. Serum cotinine levels, smoking, and periodontal attachment loss. J Dent Res 1996: 75: 796 802. 61. Gottlow J, Nyman S. Barrier membranes in the treatment of periodontal defects. Curr Opin Periodontol 1996: 3: 140148. 62. Goultschin J, Cohen HD, Donchin M, Brayer L, Soskolne WA. Association of smoking with periodontal treatment needs. J Periodontol 1990: 61: 364367. 63. Graves DT, Jiang Y. Chemokines, a family of chemotactic cytokines. Crit Rev Oral Biol Med 1995: 6: 109118. 64. Grevstad HJ, Leknes KN. Ultrastructure of plaque associated with polytetrauoroethylene (PTFE) membranes used for guided tissue regeneration. J Clin Periodontol 1993: 20: 193198. 65. Grossi SG, Zambon JJ, Ho AW. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994: 65: 260267.

38

Outcome of therapy for osseous lesions

66. Grossi SG, Genco RJ, Machtei EE. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995: 66: 2329. 67. Grossi SG, Skrepcinski FB, DeCaro T, Zambon JJ, Cummins D, Genco RJ. Response to periodontal therapy in diabetics and smokers. J Periodontol 1996: 67(suppl): 10941102. 68. Grossi SG, Zambon J, Machtei EE, Schifferle R, Andreana S, Genco RJ, Cummins D, Harrap G. Effects of smoking and smoking cessation on healing after mechanical periodontal therapy. J Am Dent Assoc 1997: 128: 599607. 69. Gu YD, Zhang GM, Zahng LY, Li FG, Jiang JF. Clinical and experimental studies of cigarette smoking in microvascular tissue transfers. Microsurgery 1993: 14: 391397. 70. Guillemin MR, Mellonig JT, Brunsvold MA. Healing in periodontal defects treated by decalcied freeze-dried bone allografts in combination with ePTFE membranes. I. Clinical and scanning electron microscope analysis. J Clin Periodontol 1993: 20: 528536. 71. Haber J, Kent RL. Cigarette smoking in a periodontal practice. J Periodontol 1992: 63: 100106. 72. Haber J, Wattles J, Crowley M, Mandell R, Joshipura K, Kent RL. Evidence for cigarette smoking as a major risk factor for periodontitis. J Periodontol 1993: 64: 1623. 73. Haeney M. Infection determinants at extremes of age. J Antimicrob Chemother 1994: 34(suppl A): 19. 74. Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Periodontol 2000 1994: 5: 78111. 75. Harrington GW. The perio-endo question: differential diagnosis. Dent Clin North Am 1979: 23: 673690. n L. Periodontal healing following experimental in76. Hellde jury to root surfaces of human teeth. Scand J Dent Res 1972: 80: 197205. 77. Hoag PM. Occlusal treatment. In: Nevins M, Becker W, Kornman K, ed. Proceedings of the World Workshop in Clinical Periodontics. Chicago: American Academy of Periodontology, 1989: Section 3: 114. 78. Hou GL, Tsai CC. Cervical enamel projection and intermediate bifurcational ridge correlated with molar furcation involvements. J Periodontol 1997: 68: 687693. 79. Hugoson A, Thorstensson H, Falk H, Kuylenstierna J. Periodontal conditions in insulin-dependent diabetics. J Clin Periodontol 1989: 16: 215223. 80. Hugoson A, Ravald N, Fornell J, Johard G, Teiwik A, Gottlow J. Treatment of class II furcation involvements in humans with bioresorbable and non-resorbable guided tissue regeneration barriers. A randomized multi-center study. J Periodontol 1995: 66: 624634. 81. Iacopino AM. Diabetic periodontitis: possible lipid-induced defect in tissue repair through alteration of macrophage phenotype and function. Oral Dis 1995: 1: 214229. 82. Imfeld T. Prevalence and quality of endodontic treatment in an elderly urban population of Switzerland. J Endod 1991: 17: 604607. 83. Ishikawa I, Nakashima K, Koseki T, Nagasawa T, Watanabe H, Arakawa S, Nitta H, Nishihara T. Induction of the immune response to periodontopathic bacteria and its role in the pathogenesis of periodontitis. Periodontol 2000 1997: 14: 79111. 84. Isidor F, Karring T. Long-term effect of surgical and nonsurgical periodontal treatment. J Periodontal Res 1986: 21: 462472. 85. Ismail AI, Burt BA, Eklund SA. Epidemiologic patterns of smoking and periodontal disease in the United States. J Am Dent Assoc 1983: 106: 617621. 86. Jansson L, Ehnevid H, Lindskog S, Blomlo f L. Relationship between periapical and periodontal status. A clinical retrospective study. J Clin Periodontol 1993: 20: 117123. 87. Jansson L, Ehnevid H, Lindskog S, Blomlo f LB. Radiographic attachment in periodontitis-prone teeth with endodontic infection. J Periodontol 1993: 64: 947953. f L. The inu88. Jansson L, Ehnevid H, Vlindskog S, Blomlo ence of endodontic infection on progression of marginal bone loss in periodontitis. J Clin Periodontol 1995: 22: 729734. 89. Kaldahl WB, Kalkwarf KL, Patil KD, Molvar MP, Dyer JK. Long-term evaluation of periodontal therapy. I. Response to 4 therapeutic modalities. J Periodontol 1996: 67: 93 102. 90. Kaldahl WB, Kalkwarf KL, Patil KD, Molvar MP, Dyer JK. Long-term evaluation of periodontal therapy. II. Incidence of sites breaking down. J Periodontol 1996: 67: 103 108. 91. Kaldahl WB, Johnson GK, Patil KD, Kalkwarf KL. Levels of cigarette consumption and response to periodontal therapy. J Periodontol 1996: 67: 675681. 92. Kalkwarf KL. Surgical treatment of periodontal diseases: access aps, bone resection techniques, root preparation and ap closure. Curr Opin Dent 1991: 1: 8792. 93. Kenny EB, Kraal JH, Saxe SR, Jones J. The effect of cigarette smoke on human oral polymorphonuclear leukocytes. J Periodontal Res 1977: 12: 227234. 94. Kepic TJ, OLeary TJ, Kafrawy AH. Total calculus removal: an attainable objective. J Periodontol 1990: 61: 1620. 95. Kerekes K, Olsen I. Similarities in the microoras of root canals and deep periodontal pockets. Endod Dent Traumatol 1990: 6: 15. 96. Kiritsy CP, Lynch SE. Role of growth factors in cutaneous wound healing: A review. Crit Rev Oral Biol Med 1993: 4: 729760. 97. Knighton DR, Fiegel VD. Growth factors and comprehensive surgical care of diabetic wounds. Curr Opin Gen Surg 1993: 3239. 98. Kobayashi T, Hayashi A, Yoshikawa R, Okuda K, Hara K. The microbial ora from root canals and periodontal pockets of non-vital teeth associated with advanced periodontitis. Int Endod J 1990: 23: 100106. e H. The role of local factors in the etiology 99. Kornman K, Lo of periodontal diseases. Periodontol 2000 1993: 2: 8397. 100. Kornman KS, Crane A, Wang H-Y, di Giovine FS, Newman MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997: 24: 7277. 101. Kornman KS, di Giovine FS. Genetic variations in cytokine expression: a risk factor for severity of adult periodontitis. Ann Periodontol 1998: 3: 327338. 102. Kwiatkowski TC, Hanley EN Jr, Ramp WK. Cigarette smoking and its orthopedic consequences. Am J Orthop 1996: 25: 590597. 103. Leknes KN. The inuence of anatomic and iatrogenic root surface characteristics on bacterial colonization and periodontal destruction: a review. J Periodontol 1997: 68: 507 516. 104. Levine RA, Kutalek KM. Guided tissue regeneration in the treatment of localized juvenile periodontitis a multi-

39

Kornman & Robertson

disciplinary approach in improving anterior esthetics: a case report. Compendium Cont Educ Dent 1993: 14: 622 630. Lima LA, Anderson FB, Wang MM, Nasjleti CE, Morrison EC, Kon S, Caffesse RG. Healing of intrabony defects and its relationship to root canal therapy: a histologic and histometric study in dogs. J Periodontol 1997: 68: 240248. Linden GJ, Mullally BH. Cigarette smoking and periodontal destruction in young adults. J Periodontol 1994: 65: 718723. Lindhe J, Svanberg G. Inuence of trauma from occlusion on progression of experimental periodontitis in the beagle dog. J Clin Periodontol 1974: 1: 314. Lindhe J, Ericsson I. The inuence of trauma from occlusion on reduced but healthy periodontal tissues in dogs. J Clin Periodontol 1976: 3: 110122. Lindhe J, Westfelt E, Nyman S, Socransky SS, Heijl L, Bratthall G. Long-term effect of surgical/non-surgical treatment of periodontal disease. J Clin Periodontol 1984: 11: 448458. Ling LJ, Lai YH, Hwang H, Chen H. Response of regenerative tissues to plaque: a histological study in monkeys. J Periodontol 1994: 65: 781787. Listgarten MA, Ellegaard B. Electron microscopic evidence of a cellular attachment between junctional epithelium and dental calculus. J Periodontal Res 1973: 8: 143150. Low CK, Tan SK. Infection in diabetic patients with ankle fractures. Ann Acad Med Singapore 1995: 24: 353355. Lu H, Wang M, Gunsolley JC, Schenkein HA, Tew JG. Serum immunoglobulin G subclass concentrations in periodontally healthy and diseased individuals. Infect Immun 1994: 62: 16771682. Lynch SE, Williams RC, Polson AM, Howell TH, Reddy MS, Zappa UE, Antoniades HN. A combination of platelet-derived and insulin-like growth factors enhances periodontal regeneration. J Clin Periodontol 1989: 16: 545 548. Lynch SE, de Castilla GR, Williams RC, Kiritsy CP, Howell TH, Reddy MS, Antoniades HN. The effects of short-term application of a combination of platelet-derived and insulin-like growth factors on periodontal wound healing. J Periodontol 1991: 62: 458467. Machtei EE, Norderyd J, Koch G, Dunford R, Grossi S, Genco RJ. The rate of periodontal attachment loss in subjects with established periodontitis. J Periodontol 1993: 64: 713718. Machtei EE, Cho MI, Dunford R, Norderyd J, Zambon JJ, Genco RJ. Clinical microbiological, and histological factors which inuence the success of regenerative periodontal therapy. J Periodontol 1994: 65: 154161. Machtei EE, Schallhorn RG. Successful regeneration of mandibular class II furcation defects: an evidence-based treatment approach. Int J Periodontics Restorative Dent 1995: 15: 146167. Mandell RL, DiRienzo J, Kent R, Joshipura K, Haber J. Microbiology of healthy and diseased periodontal sites in poorly controlled insulin dependent diabetics. J Periodontol 1992: 63: 274279. Marazita ML, Burmeister JA, Gunsolley JC, Koertge TE, Lake K, Schenkein HA. Evidence for autosomal dominant inheritance and race-specic heterogeneity in early-onset periodontitis. J Periodontol 1994: 65: 623630. 121. Marazita ML, Lu H, Cooper ME, Quinn SM, Zhang J, Bermeister JA, Califano JV, Pandey JP, Schenkein HA, Tew JG. Genetic segregation analyses of serum IgG2 levels. Am J Hum Genet 1996: 58: 10421049. 122. Marks SC, Mehta NR. Lack of effect of citric acid treatment of root surfaces on the formation of new connective tissue attachment. J Clin Periodontol 1986: 13: 109116. 123. Mashimo PA, Yamamota Y, Slots J, Park BH, Genco RJ. The periodontal microora of juvenile diabetics. Culture, immunouoresence and serum antibody studies. J Periodontol 1983: 54: 420430. 124. McCulloch CAG. Basic considerations in periodontal wound healing to achieve regeneration. Periodontol 2000 1993: 1: 1625. 125. McGuire MK. Prognosis versus actual outcome: a longterm survey of 100 treated periodontal patients under maintenance care. J Periodontol 1991: 62: 5158. 126. McGuire MK, Nunn ME. Prognosis versus actual outcome. II. The effectiveness of clinical parameters in developing an accurate prognosis. J Periodontol 1996: 67: 658865. 127. McGuire MK, Nunn ME. Prognosis versus actual outcome. III. The effectiveness of clinical parameters in accurately predicting tooth survival. J Periodontol 1996: 67: 666674. 128. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995: 9: 19. 129. Miller PD. Root coverage with the free gingival graft. Factors associated with incomplete coverage. J Periodontol 1987: 58: 674681. 130. Mombelli A, Lang NP, Nyman S. Isolation of periodontal species after guided tissue regeneration. J Periodontol 1993: 64: 11711175. 131. Mombelli A, Zappa U, Bragger U, Lang NP. Systemic antimicrobial treatment and guided tissue regeneration. Clinical and microbiological effects in furcation defects. J Clin Periodontol 1996: 23: 386396. 132. Morris ML. The reattachment of human periodontal tissues following surgical detachment: a clinical and histological study. J Periodontol 1953: 24: 220228. 133. Morris ML. Healing of human periodontal tissues following surgical detachment from non-vital teeth. J Periodontol 1957: 28: 222238. 134. Mosley LH, Finseth F, Goody M. Nicotine and its effect on wound healing. Plast Reconstr Surg 1978: 61: 570575. 135. Netscher DT, Clamon J. Smoking: adverse effects on outcomes for plastic surgical patients. Plast Surg Nursing 1994: 14: 205210. 136. Newman MG. The role of infection and anti-infection treatment in regenerative therapy. J Periodontol 1993: 64(suppl): 11661170. 137. Nowzari H, Slots J. Microorganisms in polytetrauoroethylene barrier membranes for guided tissue regeneration. J Clin Periodontol 1994: 21: 203210. 138. Nowzari H, Matian F, Slots J. Periodontal pathogens on polytetrauoroethylene membrane for guided tissue regeneration inhibit healing. J Clin Periodontol 1995: 22: 469474. 139. Nowzari H, London R, Slots J. The importance of periodontal pathogens in guided periodontal tissue regeneration and guided bone regeneration. Compendium Cont Educ Dent 1995: 16: 10421058. 140. Nowzari H, Smith MacDonald E, Flynn J, London RM, Morrison JL, Slots J. The dynamics of microbial coloniza-

105.

106.

107.

108.

109.

110.

111.

112. 113.

114.

115.

116.

117.

118.

119.

120.

40

Outcome of therapy for osseous lesions

tion of barrier membranes for guided tissue regeneration. J Periodontol 1996: 67: 694702. Nyman S, Lindhe J, Rosling B. Periodontal surgery in plaque-infected dentitions. J Clin Periodontol 1977: 4: 240249. Nyman S, Lindhe J, Karring T. Healing following surgical treatment and root demineralization in monkeys with periodontal disease. J Clin Periodontol 1981: 8: 249258. n L, Salonen L, Langeland K. Prevalence Odesjo B, Hellde of previous endodontic treatment, technical standard and occurrence of periapical lesions in a randomly selected adult, general population. Endod Dent Traumatol 1990: 6: 265272. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol 1996: 1: 821878. Okumura M, Okuda T, Nakamura T, Yajima M. Effect of basic broblast growth factor on wound healing in healing-impaired animal models. Arzneimittelforschung 1996: 46: 547551. OLeary TJ. The impact of research on scaling and root planing. J Periodontol 1986: 57: 6975. Oliver RC, Tervonen T. Periodontitis and tooth loss: comparing diabetics with the general population. J Am Dent Assoc 1993: 124: 7176. Page RC, Schroeder HE. Periodontitis in man and other animals. A comparative review. Basel: Karger, 1982. Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000 1997: 14: 911. Page RC, Offenbacher S, Schroeder HE, Seymour GJ, Kornman KS. Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontol 2000 1997: 14: 216248. Palcanis KG. Surgical pocket therapy. Ann Periodontol 1996: 1: 589617. Passariello C, Thaller MC, Selan L, Berlutti F, de Luca M, Renzini G. Periodontal regeneration procedures may induce colonization by glycoralyx-producing bacteria. Med Microbiol Immunol 1991: 180: 6772. Patters MR, Landesberg RL, Johansson LA, Trummel CL, Robertson PG. Bacteroides gingivalis antigens and bone resorbing activity in root surface fractions of periodontally involved teeth. J Periodontal Res 1982: 17: 122 130. Perlmutter S, Tagger M, Tagger E, Abram M. Effect of the endodontic status of the tooth on experimental periodontal reattachment in baboons: a preliminary investigation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987: 63: 232236. Phillips GD, Stone AM. PDGF-BB induced chemotaxis is impaired in aged capillary endothelial cells. Mech Ageing Dev 1994: 73: 189196. Pihlstrom BL, McHugh RB, Oliphant TH, Ortiz-Campos C. Comparison of surgical and nonsurgical treatment of periodontal disease: A review of current studies and additional results after 612 years. J Clin Periodontol 1983: 10: 524541. Pineda F, Kuttler Y. Mesiodistal and buccolingual roentgenographic investigation of 7275 root canals. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1972: 33: 101110. Pinson M, Hoffman WH, Garnick JJ, Litaker MS. Periodontal disease and type 1 diabetes mellitus in children and adolescents. J Clin Periodontol 1995: 22: 118123. 159. Polson AM. Trauma and progression of marginal periodontitis in squirrel monkeys. J Periodontal Res 1974: 9: 108113. 160. Polson AM, Meitner SW, Zander HA. Trauma and progression of marginal periodontitis in squirrel monkeys. IV. Reversibility of bone loss due to trauma alone and trauma superimposed upon periodontitis. J Periodontal Res 1976: 11: 290298. m J. Occurrence of gingival bleeding 161. Preber H, Bergstro in smoker and non-smoker patients. Acta Odontol Scand 1985: 43: 315320. 162. Preber H, Bergstro m J. Effect of non-surgical treatment on gingival bleeding in smokers and non-smokers. Acta Odontol Scand 1986: 44: 8589. m J. Effect of non-surgical treatment 163. Preber H, Bergstro on periodontal pockets in smokers and non-smokers. J Clin Periodontol 1986: 13: 319323. 164. Preber H, Bergstro m J. Effect of cigarette smoking on periodontal healing following surgical therapy. J Clin Periodontol 1990: 17: 324328. m J, Linder LE. Occurrence of periopa165. Preber H, Bergstro thogens in smoker and non-smoker patients. J Clin Periodontol 1992: 19(part 1): 667671. 166. Preber H, Linder L, Bergstro m J. Periodontal healing and periopathogenic microora in smokers and non-smokers. J Clin Periodontol 1995: 22: 946952. 167. Prichard J. A technique for treating intrabony pockets based on alveolar process morphology. Dent Clin North Am 1960: 85: 1. 168. Prichard JF. Advanced periodontal disease: surgical and prosthetic management. 2nd edn. Philadelphia: W.B. Saunders, 1972. 169. Rabbani GM, Ash MM, Caffesse RG. The effectiveness of subgingival scaling and root planing in calculus removal. J Periodontol 1991: 52: 119123. 170. Ramfjord SP, Caffesse RG, Morrison EC, Hill RW, Kerry GJ, Appleberry EA, Nissle RR, Stults DL. Four modalities of periodontal treatment compared over 5 years. J Clin Periodontol 1987: 14: 445452. 171. Rams TE, Listgarten MA, Slots J. Utility of 5 major putative periodontal pathogens and selected clinical parameters to predict periodontal breakdown in patients on maintenance care. J Clin Periodontol 1996: 23: 346354. 172. Ranney R. Pathogenesis of periodontal diseases. In: Klav e H, Page R, Stern I, Thorpe J, Baran B, Genco R, Lo rington E, ed. International Conference on Research in the Biology of Periodontal Disease. Springeld: University of Illinois, 1977: 222307. 173. Rees TD, Liverett DM, Guy CL. Detrimental effects of cigarette smoking on skin ap survival in the face lift patient. Plast Reconstr Surg 1984: 73: 911915. 174. Reinhardt RA, Johnson GK, Tussing GL. Root planing with interdental papilla reection and ber optic illumination. J Periodontol 1985: 56: 721726. 175. Reiser K, McGee C, Rucker R, McDonald R. Effects of aging and caloric restriction on extracellular matrix biosynthesis in a model of injury repair in rats. J Gerontol 1995: 50A: B4047. us R, Egelberg J. Healing after treatment 176. Renvert S, Nilve of periodontal intraosseous defects. V. Effect of root planning versus ap surgery. J Clin Periodontol 1985: 12: 619 629. 177. Reynolds MA, Bowers GM. Periodontal regeneration fol-

141.

142.

143.

144. 145.

146. 147.

148. 149. 150.

151. 152.

153.

154.

155.

156.

157.

158.

41

Kornman & Robertson

lowing surgical treatment. Curr Opin Periodontol 1996: 3: 126139. Reynolds JJ, Meikle MC. Mechanisms of connective tissue matrix destruction in periodontitis. Periodontol 2000 1997: 14: 144157. Ripamonti U, Reddi AH. Periodontal regeneration: Potential role of bone morphogentic proteins. J Periodontal Res 1994: 29: 225235. Robertson PB. The residual calculus paradox. J Periodontol 1990: 61: 6566. Robinson P. Evaluation of therapy. In: Klavan B, Genco R, Lo e H, Page R, Stern I, Thorpe J, Barrington E, ed. International Conference on Research in the Biology of Periodontal Disease. Springeld: University of Illinois, 1977: 377438. Robinson PJ, Guernsey LH, ed: Clinical transplantation in dental specialties. St. Louis: Mosby, 1980. Rosenberg ES, Cutler SA. The effect of cigarette smoking on the long-term success of guided tissue regeneration: a preliminary study. Ann R Australasian Coll Dent Surg 1994: 12: 8993. Rosenberg MM. Management of osseous defects, furcation involvements and periodontal-pulpal lesions. New York: Harper and Row, 1979. Rosling B, Nyman S, Lindhe J. The effect of systematic plaque control on bone regeneration in infrabony pockets. J Clin Periodontol 1976: 3: 3853. Rutherford RB, Niekrash CE, Kennedy JE, Charette MF. Platelet-derived and insulin-like growth factors stimulate regeneration of periodontal attachment in monkeys. J Periodontal Res 1992: 27: 285290. Rutherford RB, Ryan ME, Kennedy JE, Tucker MM, Charette MF. Platelet derived growth factor and desamethasone combined with a collagen matrix induced regeneration of the periodontium in monkeys. J Clin Periodontol 1995: 12: 537544. Rylander H, Ramberg P, Blohme G, Lindhe J. Prevalence of periodontal disease in young diabetics. J Clin Periodontol 1987: 14: 3843. Saffar J, Lasfargues J, Cherruau M. Alveolar bone and the alveolar process: the socket that is never stable. Periodontol 2000 1997: 13: 7690. Safkan-Seppa la B, Ainamo J. Periodontal conditions in insulin-dependent diabetes mellitus. J Clin Periodontol 1992: 19: 2429. Saito A, Hosaka Y, Nakagawa T, Seida K, Yamada S, Okuda K. Locally delivered minocycline and guided tissue regeneration to treat post-juvenile periodontitis. A case report. J Periodontol 1994: 65: 835839. Sander L, Frandsen EV, Arnbjerg D, Warrer K, Karring T. Effect of local metronidazole application on periodontal healing following guided tissue regeneration. Clinical ndings. J Periodontol 1994: 65: 914920. Sander L, Karring T. New attachment and bone formation in periodontal defects following treatment of submerged roots with guided tissue regeneration. J Clin Periodontol 1995: 22: 295299. Sanders JJ, Sepe WW, Bowers GM, Kock RW, Williams JE, Lekas JS, Mellonig JT, Pelleu GB, Gambill V. Clinical evaluation of freeze-dried bone allografts in periodontal osseous defects. 3. Composite freeze-dried bone allografts with and without autogenous bone grafts. J Periodontol 1983: 54: 18. 195. Sastrowijoto SH, Hillemans P, van Steenbergen TJM, Abraham-Inpijn L, de Graaff J. Periodontal condition and microbiology of healthy and diseased periodontal pockets in type 1 diabetes mellitus patients. J Clin Periodontol 1989: 16: 316322. 196. Sawant JM. Biochemical changes in polymorphonuclear leucocytes in diabetic patients. J Postgrad Med 1993: 39: 183186. 197. Schenkein HA, Van Dyke TE. Early-onset periodontitis: systemic aspects of etiology and pathogenesis. Periodontol 2000 1994: 6: 725. 198. Schroeder HE. Discussion: pathogenesis of periodontitis. J Clin Periodontol 1986: 13: 426430. 199. Schwartz Z, Goultschin J, Dean DD, Boyan BD. Mechanisms of alveolar bone destruction in periodontitis. Periodontol 2000 1997: 14: 158172. 200. Selvig KA, Kersten B, Chamberlain ADH, Wikesjo UME, s RE. Regenerative surgery of intrabony periodontal Nilveu defects using ePTFE membranes. Scanning electron microscopic evaluation of retrieved membranes versus clinical healing. J Periodontol 1992: 63: 974978. UM. Surgical treatment of 201. Selvig KA, Kersten BG, Wikesjo intrabony periodontal defects using expanded polytetrauoroethylene barrier membranes: Inuence of defect conguration on healing responses. J Periodontol 1993: 64: 730733. us RE, Fitzmorris L, Kersten BG, Khorsan202. Selvig KA, Nilve di SS. Scanning electron microscopic observations of cell populations and bacterial contamination of membranes used for guided tissue regeneration in humans. J Periodontol 1996: 61: 515520. 203. Sherman PR, Hutchens LH, Jewson LG. The effectiveness of subgingival scaling and root planing. Part II. J Periodontol 1990: 61: 915. 204. Shigeno Y, Ashton BA. Human bone-cell proliferation in vitro decreases with human donor age. J Bone Joint Surg [Br] 1995: 77: 139142. 205. Shlossman M, Knowler WC, Pettitt DK, Genco RJ. Type 2 diabetes mellitus and periodontal disease. J Am Dent Assoc 1990: 121: 532536. 206. Siana JE, Rex S, Gottrup F. The effect of cigarette smoking on wound healing. Scand J Plast Reconstr Surg Hand Surg 1989: 23: 207209. 207. Simion M, Trisi P, Maglione M, Piatelli A. A preliminary report on a method for studying the permeability of ePTFE membranes to bacteria in vitro. A scanning electron microscopic and histologic study. J Periodontol 1994: 65: 755761. 208. Simion M, Baldoni M, Rossi P, Zaffe D. A comparative study of the effectiveness of ePTFE membranes with and without early exposure during the healing period. Int J Periodontics Restorative Dent 1994: 14: 167180. 209. Simion M, Trisi P, Maglione M, Piattelli A. Bacterial penetration in vitro through GTAM membrane with and without topical chlorhexidine application. A light and scanning electron microscopic study. J Clin Periodontol 1995: 22: 321331. 210. Sindermann J, Kruse A, Frercks HJ, Schutz RM, Kirchner H. Investigations of the lymphokine system in elderly individuals. Mech Ageing Dev 1993: 70: 149159. 211. Sirirat M, Kasetsuwan J, Jeffcoat MK. Comparison between 2 surgical techniques for the treatment of earlyonset periodontitis. J Periodontol 1996: 67: 603607.

178.

179.

180. 181.

182. 183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

42

Outcome of therapy for osseous lesions

212. Slaughter MS, Olson MM, Lee JT Jr, Ward HB. A fteenyear wound surveillance study after coronary artery bypass. Ann Thorac Surg 1993: 56: 10631068. 213. Smith JE, Holtzman S, Matheson JE. Structuring conditional relationships in inuence diagrams. Operations Res 1993: 41: 280297. 214. Smitherman KO, Peacock JE Jr. Infectious emergencies in patients with diabetes mellitus. Med Clin North Am 1995: 79: 5377. 215. Stoltenberg JL, Osborn JB, Pihlstrom BL, Herzberg MC, Aeppli DM, Wolff LF, Fisher GE. Association between cigarette smoking, bacterial pathogens and periodontal status. J Periodontol 1993: 64: 12251230. 216. Svanberg GK, King GJ, Gibbs CH. Occlusal considerations in periodontology. Periodontol 2000 1995: 9: 106117. 217. Sweet JB, Butler DP. Effect of smoking on the incidence of localized osteitis following mandibular third molar surgery. Quintessence Int 1978: 2: 910. 218. Tal H. Relationship between interproximal distance of roots and the prevalence of intrabony pockets. J Periodontol 1984: 55: 604607. 219. Tanaka E, Ase K, Okuda T, Okumura M, Nogimori K. Mechanism of acceleration of wound healing by basic broblast growth factor in genetically diabetic mice. Biol Pharmacol Bull 1996: 19: 11411148. 220. Tanner ACR, Visconti RA, Holdeman LV, Sundqvist G, Socransky SS. Similarity of Wolinella recta strains isolated from periodontal pockets and root canals. J Endod 1982: 8: 294300. 221. Tempro PJ, Nalbandian J. Colonization of retrieved polytetrauoroethylene membranes: morphological and microbiological observations. J Periodontol 1993: 64: 162168. 222. Tervonen T, Knuuttila M, Pohjamo L, Nurkkala H. Immediate response to non-surgical periodontal treatment in subjects with diabetes mellitus. J Clin Periodontol 1991: 18: 6568. 223. Tervonen T, Oliver RC, Wolff LF, Bereuter J, Anderson L, Aeppli DM. Prevalence of periodontal pathogens with varying metabolic control of diabetes mellitus. J Clin Periodontol 1994: 21: 375379. 224. Thorstensson H, Hugoson A. Periodontal disease experience in adult long-duration insulin-dependent diabetics. J Clin Periodontol 1993: 20: 352358. 225. Tonetti M, Pini Prato G, Cortellini P. Periodontal regeneration of human infrabony defects. IV. Determinants of healing response. J Periodontol 1993: 64: 934940. 226. 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. 227. Tonetti MS, Pini Prato G, Cortellini P. Factors affecting the healing response of intrabony defects following guided tissue regeneration and access ap surgery. J Clin Periodontol 1996: 23: 548556. 228. Van de Kerkhof PC, Van Bergen B, Spruijt K, Kuiper JP. Age-related changed in wound healing. Clin Exp Dermatol 1994: 19: 369374. Waerhaug J. Epidemiology of periodontal disease: review of literature. In: Ramfjord SP, Kerr DA, Ash MM, ed. World Workshop in Periodontics. Ann Arbor: University of Michigan, 1966: 181211. Waerhaug J. The angular bone defect and its relationship to trauma from occlusion and down-growth of subgingival plaque. J Clin Periodontol 1979: 6: 6182. Wang HL, Yuan K, Burgett F, Shyr Y, Syed S. Adherence of oral microorganisms to guided tissue membranes: an in vitro study. J Periodontol 1994: 65: 211218. Weiger R, Hitzler S, Hermle G, Lo st C. Periapical status, quality of root canal llings and estimated endodontic treatment needs in an urban German population. Endod Dent Traumatol 1997: 13: 6974. G, Jonasson P, Lindhe J. Westfelt E, Rylander H, Blohme The effect of periodontal therapy in diabetics. Results after 5 years. J Clin Periodontol 1996: 23: 92100. Wilson ME, Hamilton RG. Immunoglobulin G subclass response of juvenile periodontitis subjects to principal outer membrane proteins of Actinobacillus actinomycetemcomitans. Infect Immun 1995: 63: 10621069. Wilson ME, Bronson PM, Hamilton RG. Immunoglobulin G2 antibodies promote neutrophil killing of Actinobacillus actinomycetemcomitans. Infect Immun 1995: 63: 10701075. Wilson ME, Kalmar JR. Fc-gamma-RIIA (DC32) a potential marker dening susceptibility to localized juvenile periodontitis. J Periodontol 1996: 67: 323331. Wu L, Brucker M, Gruskin E, Roth SI, Mustoe TA. Differential effects of platelet-derived growth factor BB in accelerating wound healing in aged versus young animals: the impact of tissue hypoxia. Plast Reconstr Surg 1997: 99: 815822: 823824. Yilmaz S, Kuru B. A regenerative approach to the treatment of severe osseous defects: report of an early onset periodontitis case. Periodontal Clin Invest 1996: 18: 13 16. Zambon JJ, Reynolds H, Fisher JG, Shlossman M, Dunford R, Genco RJ. Microbiological and immunological studies of adult periodontitis in patients with noninsulin-dependent diabetes mellitus. J Periodontol 1988: 59: 2331. Zambon JJ. Periodontal diseases: microbial factors. Ann Periodontol 1996: 1: 879925. Zambon JJ, Grossi SG, Machtei EE, Ho AW, Dunford R, Genco RJ. Cigarette smoking increases the risk of subgingival infection with periodontal pathogens. J Periodontol 1996: 67(suppl): 10501054. Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 1997: 63: 356361.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240. 241.

242.

43