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Saving teeth has been more than a manifesto for legions of periodontists over the years; it has been an overarching goal for dentistry. In recent years, several technological advancements have made this goal significantly more attainable, most notably in the realm of periodontal regeneration and regenerative medicine, which reconstruct the tooth-supporting structures of the periodontal ligament, cementum, gingiva, and alveolar bone. Although forms of periodontal regeneration have been around for decades, modern-day innovations transformed the possibilities to clinical realities for patients and practitioners alike.
In June 2014, 52 international clinicians, researchers, and educators convened in Chicago, Illinois, to assess state-of-the-science literature about regeneration during the American Academy of Periodontology’s (AAP’s) Enhancing Periodontal Health Through Regenerative Approaches workshop. In addition to revisiting the biologic mechanisms and clinical practice of saving teeth, participants developed practical applications based on therapeutic advancements and identified directions for future study.
The AAP convened this think tank of global experts at a time when prevalence of periodontal breakdown was at alarmingly high levels in the United States. Research from a Centers for Disease Control and Prevention (CDC) study conducted between 2009 and 2012 indicates that nearly 50% of the US population older than 30 years of age has some form of periodontal disease.1 Most frequently, older patients present with periodontal disease; 70% of American adults aged 65 and older experience destructive periodontitis,2 which is displayed by bone erosion and extensive attachment loss. Moderate and severe cases of periodontitis are seen in 38% of the US adult population.
Preserving a patient’s natural dentition while halting the advancement of disease goes beyond the realm of oral esthetics and function. Timely, evidence-based treatment may contribute to a patient’s overall wellbeing. A growing body of evidence links periodontal disease to systemic ailments; for example, an independent association has been found between moderate to severe periodontitis and the increased risk or onset of diabetes.3 Epidemiologic evidence suggests that periodontitis also confers a heightened risk for future cardiovascular disease.4 Although further study is required in understanding periodontal disease’s additional associations with chronic obstructive pulmonary disease, pneumonia, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome, and cancer,5 initial assessments of the perio-systemic link identify inflammation as the commonality that periodontal disease and these conditions share.
Regenerative periodontal procedures are not specifically designed to slow the progression of infection but instead restore soft tissue and hard tissue already lost to disease,6 either to protect a patient’s natural dentition or to prepare the infected sites for the future installation of a tooth replacement implant. However, existing inflammation may be reduced in the biologic process of tissue regrowth and removal of disease-laden tissues.
Types of Periodontal Regeneration Techniques
Many emerging periodontal regeneration techniques, including those using cell-delivery systems, scaffolding matrices, bone anabolic agents, and mesenchymal stem cells, are in an early preclinical stage and require additional scientific investigation. Hard tissue procedures rebuild the bone, ligament, and root cementum that anchor a tooth in place. Soft tissue procedures spur the growth of new gingival tissue in areas of recession, improving the esthetic appearance of the gums.
The three types of regenerative therapies that are frequently used in the clinical setting are bone grafting, biologic agents, and guided tissue regeneration (GTR).
Bone Grafting
Bone grafting, which has been a long-used regenerative procedure, uses tissue taken from the patient (autografts), another human source from a tissue bank (allografts), another species (xenografts), or synthetic man-made material (alloplasts) to generate new bone structures, later to be absorbed by the body and replaced by new tissue over a period of time.
GTR
GTR uses a barrier membrane to protect and stabilize the blood clot created in the healing process of a regenerative procedure,7,8 such as a bone graft. Any impediments to the blood clot and other parts of the healing and subsequent regenerative process can result in partial wound repair by scar tissue instead of the new bone and ligament. Protective membranes can be either resorbable, which may work best for periodontal applications, or non-resorbable, which may work best for reconstruction of the alveolar ridge in preparation for the placement of a dental implant.
Resorbable membranes do not require a follow-up surgery for removal and come with many advantages to the patient;9 however, membranes of any kind should adhere to the considerations of resorption time and space creation for an overall successful procedure. Membranes should be malleable enough to provide adequate space for the graft containment at the defect site. In cases where the space maintenance of a membrane may be precluded by an anatomical complication, other regenerative procedures (used exclusively or in conjunction with another technique) may be considered. In the instance of resorbable membranes used with a graft, those that resorb quickly will essentially lose their function of protecting the graft, thus allowing the migration of the graft matrix and may inhibit the regenerative processes. Membranes that resorb too slowly may impede blood flow to the newly regenerated structure and be susceptible to infection, compromising the structure’s health.10
As with dental procedures of any kind, a clinician is advised to use the GTR membrane that best suits his or her patient’s condition and promotes the success of the overall procedure. Another consideration pertaining to the success of GTR is the necessary decontamination of the tooth root in the treatment area, where biofilm and cementum may accumulate.11 Like GTR procedures, which are sensitive in nature, proper disinfection of the tooth root requires specialized technical skill and focus.
Biologics
Biologic agents have demonstrated significant potential to repair periodontal wounds. Biologics include growth factors, enamel matrix derivative, and bone anabolic agents that work by stimulating cells to proliferate, migrate, stimulate matrix biosynthesis, or differentiate. In general, such agents are at an earlier stage of development; however, several have entered into the clinical arena and are used widely in periodontal practice (Table 1).12,13
Regenerative Procedures for Furcation and Intrabony Defects
Patients who are suitable candidates for regenerative procedures often present with furcation and/or intrabony defects. Furcation defects, which are classified according to measurements of attachment loss, typically refer to bone loss in the area where tooth roots meet (or fornix). Clinicians often face the decision of whether to treat the furcation defect to either preserve the involved tooth or remove the tooth and prepare the extraction site for reconstruction with a bridge or an implant.
As shown by Huynh-Ba and colleagues, the regenerative approach of GTR provides a high survival rate for a preserved tooth between 83.3% and 100% after 5 to 12 years.14 This study is an indicator of the viability of regenerative treatments in cases of furcation involvement.
Intrabony defects occur when disease has affected alveolar bone intraosseously. Lang and colleagues showed that “defect morphology of angular (intrabony) defects is generally described according to osseous wall affecting the defect,” citing Goldman and Cohen’s 1958 classification of intrabony pockets (Table 2).15
Generally, the morphology of intrabony defects is described by the osseous walls that limit the defect. However, a more biologic description of defect morphology should include the importance of the periodontal ligament. The highest goal of periodontal therapy is the regeneration of the periodontium, including new cementum apposition with inserting periodontal ligament fibers, in addition to filling defects with alveolar bone.
Reynolds and colleagues found that regenerative treatment for intrabony defects increased clinical attachment levels, reduced probing depths, and improved overall periodontal health. Improvements are said to last for more than 10 years. Treatments for intrabony defects have typically included bone replacement grafts; however, GTR, biologics, and a combination of therapies may also be effective.16
From Theory to Practice
Proceedings from the AAP’s workshop on regeneration were published in the Journal of Periodontology and included consensus reports and systematic reviews on soft tissue root and non-root coverage, intrabony defects, furcation defects, and periodontal reconstruction (Table 3).17 Accompanying practical applications were published in Clinical Advances in Periodontics, the Journal of Periodontology’s online-only, clinically-focused counterpart, designed to bridge gaps between research and real-life practice.
Methods for the treatment of gingival recession (GR) defects are a key concern in the science of periodontal regeneration. Gingival recession is a common occurrence in patients, and workshop participants agreed that the measurement of procedural outcomes could be gleaned from a reduction in defect depth, improved clinical attachment, and an increase in keratinized soft tissues. The practical application report on this subject indicates the following procedures as viable treatment options: subepithelial connective tissue graft (SCTG), coronally advanced flap, free gingival graft, and soft tissue graft substitutes, such as acellular dermal matrix, xenogeneic collagen matrix biomaterials, and biologics, including recombinant human platelet-derived growth factor and enamel matrix derivative.18 Richardson and colleagues noted, “The variability in these techniques revolves around the inclusion or avoidance of a palatal donor graft. The decision as to how to approach a specific clinical GR-type defect should be a combination of considerations relative to the clinician’s surgical goals and the patient’s understanding of the anticipated outcome. The associated systematic review19 provides clear evidence that SCTG-based procedures provide the best outcome for mean and complete root coverage, as well as an increase in KT.”18
For non-root coverage procedures, John and colleagues20 determined that patient education about plaque control and risk reduction should be coupled with gingival augmentation procedures, also stating the following:
“Understanding the clinical importance of the presence of a minimum amount of attached gingiva in patients with suboptimal hygiene is an important first step in addressing the condition. [...] An analysis of patient-specific factors will help with the appropriate choice of surgical procedures aimed at augmenting the dimension of KT/attached gingival tissue.”20
Reynolds and colleagues21 provided a practical application report for the care of intrabony defects, noting that choosing the proper treatment for the patient depends on the makeup of the defect and patient risk factors. However, a number of regenerative treatments are effective in the treatment of the condition, including combination techniques. “Non-cellular BRGs [bone replacement grafts] and GTR contribute to the architectural stability of the regenerative site and, thereby, help guide and protect clot formation and maturation; however, these regenerative approaches use principally non-biologically active materials. Therefore, multiple factors must be considered in the selection of regenerative therapy for the management of intrabony defects. In general, with increasing loss of proximity, height, and number of remaining bony walls, the selection of a regenerative approach must help address the need for architectural support, vascular ingrowth, cellular recruitment, and clot stabilization,” they wrote.21
In addition to furcation grade and location, according to Aichelmann-Reidy and colleagues,22 clinicians administering periodontal regenerative therapy should consider a patient’s systemic factors, local and anatomic qualities, and the furcation’s characteristics. The report indicates that although Class II furcation defects attain good outcomes with regenerative therapy, Class I defects can be specifically managed with combination therapy of a bone graft and barrier membrane. Regarding Class II defects, the report states that, “[a]lthough there is limited evidence for regeneration of Class III furcation defects, there may be a modest improvement allowing for tooth retention.”
Regarding emerging techniques, Lin and colleagues12 note, “At present, there are indications that emerging technologies can be used successfully for periodontal regeneration. Case reports and clinical trials are being conducted with a variety of emerging technologies. However, many are yet to be approved by a regulatory agency, or there is a lack of evidence-based literature to validate their expanded use.”
A companion consensus report by Cochran and colleagues23 on priorities for future research in the area of emerging technologies indicated that potential studies should do the following:
1. “Develop a non-invasive assessment of clinical periodontal regeneration.
Evaluate the efficacy and safety of combining emerging and/or current therapies.
2. Validate existing and/or emerging therapies being used ‘off label.’
Explore therapies developed for other purposes for their application to periodontal regeneration.
3. Define the individual’s genetic and epigenetic profile so that it can be used to personalize the choice of therapy.
4. Assess the effect of individual disease pathogenesis, etiology, and healing potential on therapeutic treatment selection.
5. Optimize the understanding of risk factors to aid in the selection of appropriate therapy and the achievement of enhanced outcomes to restore the structure and function of the periodontium.
6. Define molecular and cellular mechanisms of the emerging therapy using in vitro and in vivo models.
7. Identify developmental pathways of the periodontium for potential application in regenerative therapy.
8. Focus on developing minimally invasive technologies to minimize pain and morbidity without compromising outcomes.
9. Define what constitutes clinical success.
10. Characterize the effect of the selected therapy on the patient’s quality of life.”
Conclusion
Regenerative therapy using soft and hard tissue grafting, biologic agents, or GTR has a promising future in the periodontal specialty. A number of additional regenerative techniques, including novel cell-delivery systems, show promise but require further scientific study to determine their effectiveness. The results from the AAP Workshop on Periodontal Regeneration demonstrate the strong evidence base for reconstructive therapies that can predictably rebuild soft and hard tissues to maintain health, form, and function. The use of periodontal regenerative medicine offers an important option for tooth retention and preservation of the patient’s dentition.
Author Information
William V. Giannobile, DDS, DMSc, is the Najjar endowed professor of dentistry and biomedical engineering and chair of the department of periodontics and oral medicine at the University of Michigan School of Dentistry. Dr. Giannobile previously served as a faculty member at Harvard and Forsyth Institute in Boston. He has published and lectured extensively in the fields of regenerative medicine, tissue engineering, and salivary diagnostics as it relates to periodontal and peri-implant reconstruction. He is an editor-in-chief of the Journal of Dental Research and is on the editorial boards of multiple journals. He is a fellow of the American College of Dentists and a diplomate of the American Board of Periodontology. Dr. Giannobile is a past president of the American Academy of Periodontology Foundation and as a consultant to the Food and Drug Administration.
Pamela K. McClain, DDS, is a highly respected periodontist in the Denver metro area for both her vast contributions to periodontal research and her cutting edge level of care. She is a licensed periodontist in Colorado and California and is board certified as a diplomate of the American Board of Periodontology. Dr. McClain actively collaborates with family dentists and other dental specialists and lectures on a variety of topics at interdisciplinary dental meetings and conferences locally, nationally, and abroad. Dr. McClain is known internationally for her work in periodontal regeneration. She has given more than 70 professional presentations throughout the United States and in Europe and Asia, and is a past president of the American Academy of Periodontology.
Disclosures
William V. Giannobile, DDS, DMSc, and Pamela K. McClain, DDS, have nothing to disclose relative to this activity. The American Academy of Periodontology Foundation, the Osteology Foundation, Colgate-Palmolive, and Geistlich Pharma NA supported the AAP Workshop on Periodontal Regeneration.
Acknowledgments
The authors are indebted to Meg Dempsey and Mame Kwayie for their excellent assistance in the preparation of this article.
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About the Author
William V. Giannobile, DDS, DMSc
Department of Periodontics and Oral Medicine
University of Michigan
School of Dentistry
Ann Arbor, Michigan
Department of Biomedical Engineering
College of Engineering
University of Michigan
Ann Arbor, Michigan
Pamela K. McClain, DDS
Private Practice
Aurora, Colorado
